7-oxabicycloheptyl substituted heterocyclic amide or ester prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease

ABSTRACT

7-Oxabicycloheptane substituted prostaglandin analogs useful in treating thrombotic and vasopastic disease have the structural formula ##STR1## wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; Z is --(CH 2 ) 2  --, --CH═CH-- or ##STR2## wherein Y is O, a single bond or vinyl, with the proviso that when n is 0, if Z is ##STR3## then Y cannot be O, and Z is --CH═CH--, n is 1, 2, 3 or 4; and when Y=vinyl, n=0; R is CO 2  H, CO 2  lower alkyl, CH 2  OH, CO 2  alkali metal, CONHSOR 3 , CONHR 3a  or --CH 2  --5-tetrazolyl, X is O, S or NH; and where R 1 , R 2 , R 3  and R 3a  are as defined herein.

REFERENCE TO OTHER APPLICATIONS

The present application is a continuation-in-part of U.S. applicationSer. No. 442,818 filed Nov. 28, 1989, which is a continuation-in-part ofU.S. application Ser. No. 433,301 filed Nov. 8, 1989, which is acontinuation of U.S. Ser. No. 288,826 filed Dec. 23, 1988, and is acontinuation-in-part of U.S. application Ser. No. 334,070 filed Apr. 3,1989.

DESCRIPTION OF THE INVENTION

The present invention relates to 7-oxabicycloheptyl substitutedheterocyclic amide prostaglandin analogs which are thromboxane A₂ (TXA₂)receptor antagonists or combined thromboxane A₂ receptorantagonist/thromboxane synthetase inhibitors useful, for example, in thetreatment of thrombotic and/or vasospastic disease, and have goodduration of action. These compounds have the structural formula I##STR4## and including all stereoisomers thereof, wherein

m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

Z is --(CH₂)₂ --, --CH═CH-- or ##STR5## wherein Y is O, a single bond orvinyl (--CH═CH--), with the provisos that when n is 0, if Z is ##STR6##then Y cannot be 0; and when Z is --CH═CH--, n is 1,2,3, or 4; and whenY=vinyl, n=0;

R is CO₂ H, CO₂ lower alkyl, CO₂ alkali metal, CH₂ OH, CONHSO₂ R³,CONHR^(3a), or ##STR7## (--CH₂ --5-tetrazolyl);

X is O, S or NH;

R¹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aralkyl,aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, or amide ##STR8##wherein t is 1 to 12 and R_(a) is lower alkyl, aryl, cycloalkyl, orcycloalkylalkyl);

R² is hydrogen, lower alkyl, aryl, or aralkyl; or

R¹ and R² together with the nitrogen to which they are linked may form a5- to 8- membered ring;

R³ is lower alkyl, aryl or aralkyl; and

R^(3a) is hydrogen, lower alkyl, aryl or aralkyl.

Thus, the compounds of the invention include the following types ofcompounds: ##STR9## wherein in formulae ID, IE and IF, Z¹ is --CH═CH--or --(CH₂)₂ --.

In addition, in accordance with the present invention, a compound isprovided having the structure I_(x) ##STR10## wherein m, n, and R¹ areas defined hereinbefore except that it will not include H and R_(z) isCO₂ H, CO₂ alkyl or CO₂ alkali metal.

Preferred are compounds of formula I_(x) having the formula I_(y)##STR11## where R_(z) is CO₂ H and R¹ is cycloalkylalkyl.

The term "lower alkyl" or "alkyl" as employed herein includes bothstraight and branched chain radicals of up to 18 carbons, preferably 1to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1, 2 or 3 halo substituents, an aryl substituent, analkyl-aryl substituent, a haloaryl substituent, a cycloalkylsubstituent, an alkylcycloalkyl substituent, hydroxy or a carboxysubstituent.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groupscontaining 3 to 12 carbons, preferably 3 to 8 carbons, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may besubstituted with substituents such as halogen, lower alkyl, alkoxyand/or hydroxy group.

The term "aryl" or "Ar" as employed herein refers to monocyclic orbicyclic aromatic groups containing from 6 to 10 carbons in the ringportion, such as phenyl, naphthyl. Aryl (or Ar), phenyl or naphthyl mayinclude substituted aryl, substituted phenyl or substituted naphthyl,which may include 1 or 2 substituents on either the phenyl or naphthylsuch as lower alkyl, trifluoromethyl, halogen (Cl, Br, I or F), loweralkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl,arylthio, arylsulfinyl and/or arylsulfonyl.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinrefers to lower alkyl groups as discussed above having an arylsubstituent, such as benzyl.

The term "lower alkoxy", "alkoxy" or "aralkoxy" includes any of theabove lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herein refers to chlorine, bromine,fluorine or iodine with chlorine being preferred.

The term "lower alkenyl" or "alkenyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one double bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q) -- where q can be 1 to 14, such as 2-propenyl, 2-butenyl,3-butenyl, 2-pentenyl, 4-pentenyl and the like, and may include ahalogen substituent such as I, Cl, or F.

The term "lower alkynyl" or "alkynyl" as employed herein with respect tothe R¹ substituent includes a carbon chain of up to 16 carbons,preferably 3 to 10 carbons, containing one triple bond which will beseparated from "N" by at least one saturated carbon moiety such as--(CH₂)_(q') -- where q' can be 1 to 14, such as 2-propynyl, 2-butynyl,3-butynyl and the like.

The term "cycloheteroalkyl" as used herein as an R¹ substituent refersto a 5-, 6- or 7-membered saturated ring which includes 1 or 2 heteroatoms such as nitrogen, oxygen and/or sulfur, and which is linked to the"N" of the ##STR12## group through a carbon atom-either beta or gamma toa heteroatom, such as ##STR13## and the like.

The term "heteroaryl" or heteroaromatic as an R¹ substituent refers to a5- or 6-membered aromatic ring which includes 1 or 2 hetero atoms suchas nitrogen, oxygen or sulfur, which are not directly linked through ahetero atom to the "N" of the ##STR14## group, such as ##STR15## and thelike

The term "cycloheteroalkylalkyl" as defined by R¹ refers to 5-, 6- or7-membered saturated ring which includes 1 or 2 heteroatoms such asnitrogen, oxygen or sulfur, and is linked to the "N" of the ##STR16##group through a (CH₂)_(x) chain wherein x is 1 to 12, preferably 1 to 8,such as ##STR17##

The term "heteroarylalkyl" as defined by R¹ refers to a 5-, 6- or7-membered aromatic ring which includes 1, 2, 3 or 4 heteroatoms such asnitrogen, oxygen or sulfur, and is linked to the "N" of the ##STR18##group through a --(CH₂)_(x') -- chain where x' is 1 to 12, preferably 1to 8, such as ##STR19##

Preferred are those compounds of formula I wherein Z is ##STR20## and Xis O. More preferred are compound of formula I wherein Z- is ##STR21## mis 1, n is 1 or 2, Y is a single bond, X is O, R is CO₂ H, R¹ issubstituted alkyl or a cycloheteroalkylalkyl and R² is H or lower alkyl,and --Y--(CH₂)_(n) --R is in the ortho or meta position.

Also preferred are compounds of formula I wherein Z is --CH═CH-- in thecis configuration, m is 1, n is 2 or 3, R is CO₂ H, R¹ is substitutedphenylalkyl or cyclohexylalkyl and R² is H or methyl.

The compounds of formula I of the invention may be prepared as follows.

The various compounds of the invention wherein Z is ##STR22## may beprepared as outlined below.

Compounds of the invention where Y is a single bond, n is 1, 2, 3 or 4and X is O are prepared starting with bromophenylalkyl alcohol A##STR23## wherein n is 1, 2, 3 or 4 which is treated with a protectingcompound such as t-butylchlorodiphenylsilane, in the presence of anamine base such as triethylamine and an inert solvent, employingconventional procedures, to form the protected bromophenylalkyl compoundB ##STR24## wherein Pro represents a protecting group.

Examples of protecting compounds suitable for use herein in reactingwith bromophenalkyl alcohol A include but are not limited to ##STR25##

The protected compound B is then transmetallated by treatment with t-C₄H₉ Li or n-C₄ H₉ Li in the presence of diethyl ether or tetrahydrofuranat reduced temperature of from about -100° to about 0° C. or ispreferably subjected to a Grignard reaction by treatment with magnesiumin the presence of an inert organic solvent such as tetrahydrofuran(THF) or diethyl ether and then is condensed with(exo)octahydro-5,8-epoxy-1H-benzopyran-3-ol or(exo)octahydro-4,7-epoxyisobenzofuran-1-ol (prepared as described inU.S. Pat. No. 4,143,054) of the structure C ##STR26## employing a molarratio of C:B of within the range of from about 1:2 to about 1:4, in thepresence of an inert organic solvent such as THF at a reducedtemperature of from about -78° to about 25° C., to form the condensed7-oxabicycloheptane compound II ##STR27##

The condensed compound II is then subjected to hydrogenolysis bytreatment with hydrogen in the presence of a catalyst such as palladiumhydroxide on charcoal in acetic acid or an inert organic solvent such asethyl acetate, to form the alcohol III ##STR28##

When the protecting group (Pro) in III is thexyldimethylsilyl ort-butyldimethylsilyl, alcohol III may be subjected to acetylation bytreatment with acetyl chloride in the presence of pyridine and methylenechloride to acetylate the free alcohol and the so-formed acetate isdeprotected by conventional procedures, for example, by treatment withaqueous hydrofluoric acid in the presence of acetonitrile to cleave offthe silyl protecting group to form IIIA ##STR29## IIIA is then treatedwith a protecting compound such as t-butyldiphenylsilyl chloride in thepresence of a catalyst such as 4,4-dimethylaminopyridine and an aminesuch as triethylamine and methylene chloride to add the protecting groupand then the acetate is removed by treatment with aqueous hydroxide intetrahydrofuran or excess methyllithium in the presence of an inertsolvent such as diethyl ether to form IIIB ##STR30##

The protected alcohol IIIB is then subjected to a Jones oxidationwherein a solution of protected alcohol IIIB in acetone cooled to fromabout -10° to about 25° C. is treated with Jones reagent (that is, CrO₃dissolved or suspended in sulfuric acid in the presence of water,prepared as described in Fieser & Fieser, "Reagents for OrganicSynthesis," Vol. 1, p. 142 (1967)) to form acid IV ##STR31##

Acid IV, in an inert organic solvent, such as tetrahydrofuran, is thenmade to undergo a carbodiimide coupling reaction with aminehydrochloride ##STR32## where R⁴ is lower alkyl such as methyl or ethyl,or arylalkyl, such as benzyl, in the presence ofdicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-31-ethylcarbodiimide hydrochloride (WSC) and-hydroxybenzotriazole and triethylamine under an inert atmosphere suchas argon employing a molar ratio of D:IV of within the range of fromabout 1.2:1 to about 1:1, to form hydroxyamide V ##STR33##

Hydroxyamide V is then subjected to cyclodehydration wherein a solutionof V in an inert organic solvent such as tetrahydrofuran, acetonitrileor chloroform , under an inert atmosphere such as argon, is treated withtriphenylphosphine (employing a molar ratio of V:triphenylphosphine offrom about 0.8:1 to about 1:1) and carbon tetrachloride in the presenceof an amine base such as triethylamine or diisopropylethylamine, to formoxazoline VI ##STR34##

Oxazoline VI is oxidized by treatment with manganese dioxide orpreferably nickel peroxide (Nakagawa et al, J. Org. Chem., 1962, 27,1597) to form the oxazole VII ##STR35##

Oxazole VII is converted to the corresponding acid by treating VII witha base, such as lithium hydroxide, sodium hydroxide or potassiumhydroxide to form the corresponding alkali metal salt, followed byneutralization with an acid, such as dilute hydrochloric acid or oxalicacid to form acid compound VIII ##STR36## Acid VIII is converted to thecorresponding acid chloride by treating VIII with oxalyl chlorideoptionally in the presence of catalytic amounts of dimethylformamide,and a solvent such as benzene, toluene or methylene chloride. Theso-formed acid chloride is dissolved in an inert solvent such asmethylene chloride or toluene cooled to a temperature within the rangeof from about -10° C. to about +10° C., and amine base such astriethylamine or pyridine and amine E, or a salt thereof, are added##STR37## employing a molar ratio of E:VIII of within the range of fromabout 1.1:1 to about 1.5:1, form the oxazole IX ##STR38##

Silyl ether IX is then deprotected using conventional procedures, forexample, by treatment with aqueous hydrofluoric acid in the presence ofacetonitrile and methylene chloride and is then subjected to a Jonesoxidation employing procedures described hereinbefore to form theoxazole IG of the invention ##STR39##

In a more preferred procedure, compounds of formula I wherein Y is asingle bond, n is 1, 2, 3 or 4 and X is O may be prepared starting withalcohol III by protecting the alcohol function thereof by treatment, forexample, with a solution of acetic anhydride, pyridine and4-dimethylaminopyridine to form the protected alcohol X ##STR40##

Alternatively, compound II can be protected by treatment with, forexample, a solution of acetic anhydride and pyridine to form compound XI##STR41## which is then subjected to hydrogenolysis as described aboveto provide compound X.

The protected alcohol X wherein Pro is t-butyldimethylsilyl ordimethyl(1,1,2-trimethylpropyl)silyl is subjected to a Jones oxidationemploying procedures described hereinbefore to form crude acid which isdeacetylated by reaction with aqueous hydroxide in the presence of inertorganic solvent such as THF and then esterified, for example, bytreatment with diazoalkane, such as diazomethane, or acidic alcohol suchas methanolic HCl, to form the alcohol ester XII ##STR42##

In an alternative method for forming alcohol ester XII, protectedalcohol XI is subjected to a Jones oxidation and esterification to formester Xla ##STR43## which is then made to undergo hydrogenolysis andsubsequent removal of the acetate protecting group bytransesterification to afford alcohol ester XII.

Next, the alcohol ester XII is subjected to a Jones oxidation to formthe acid XIII ##STR44##

In an alternative procedure, acid XIII wherein n is 1, Z is ##STR45##where Y is a single bond, may be prepared from alcohol III by treatingIII with acetic anhydride in the presence of pyridine or other organicbase such as triethylamine, under an inert atmosphere such as argon, toform the corresponding acetate and treating the acetate with adeprotecting agent such as (n-C₄ H₉)₄ NF to remove the protecting groupand form acetate alcohol IIIC ##STR46##

Acetate alcohol IIIC is then made to undergo a Dess-Martin oxidation bytreating a mixture of IIIC in dry methylene chloride with Dess-Martinperiodinane (J. Org. Chem. 1983, 48, 4155) to form the aldehyde IIID##STR47## which is then oxidized by treating IIID with N-iodosuccinamide(NIS) in the presence of potassium carbonate in methanol to form acetateester IIIE ##STR48##

Acetate ester IIIE in methanol is deprotected by treatment with a weakbase such as potassium carbonate, and the resulting alcohol is thensubjected to a Jones oxidation as described herein to form acid XIII,where n is 1.

The acid XIII is then made to undergo a carbodiimide coupling reactionwith amine hydrochloride D, where R⁴ is benzyl, as describedhereinbefore (with respect to coupling of acid IV) to form the amide XIV##STR49##

Amide XIV is then subjected to cyclodehydration (using a proceduresimilar to the cyclodehydration of amide V) to form oxazoline XV##STR50## which is made to undergo oxidation using manganese dioxide, ornickel peroxide, or preferably cupric bromide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form the oxazole XVI##STR51##

The cupric bromide oxidation is carried out at a temperature of withinthe range of from about 20° C. to about 70° C., employing a molar ratioof cupric bromide to XV of within the range of from about 2:1 to about6:1 and a molar ratio of cupric bromide to DBU of within the range offrom about 1:1 to about 1:3 in an inert solvent such as ethyl acetate orpreferably ethylacetate/chloroform (1:1, v/v).

The latter oxidation is a novel method in accordance with the presentinvention.

Oxazole XVI is then deprotected to remove R⁴, for example, by treatmentwith palladium hydroxide on charcoal and hydrogen in the presence of aninert solvent such as ethyl acetate, to form the corresponding acid XVII##STR52##

Acid XVII is then converted to the corresponding acid chloride employinga procedure similar to that described with respect to acid VIII and theresulting acid chloride is treated with amine E employing a procedureand molar ratio of E:XVII similar to that described hereinbefore withrespect to acid VIII to form the ester of the invention IH ##STR53##

In an alternate preferred procedure for the preparation of IH acid XIIIis made to undergo a carbodiimide coupling reaction with amine Da##STR54## in the presence of dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole and triethylamine as described hereinbefore toform hydroxy amide XIV'. ##STR55##

Hydroxy amide XIV' is then subjected to cyclodehydration as describedhereinbefore (with respect to the preparation of VI). A preferred methodfor this conversion involves treatment of XIV' with an alkylsulfonylchloride, such as methanesulfonyl chloride in the presence of an aminesuch as triethylamine or pyridine followed by treatment of the resultingalkylsulfonate intermediate with potassium carbonate in acetone to formoxazoline XV' ##STR56## which is made to undergo oxidation as describedhereinbefore (with respect to the preparation of XVI) to form oxazoleIH.

Ester IH may then be hydrolyzed by treatment with an aqueous solution ofalkali metal base and then aqueous acid to form the corresponding acidIG.

Compounds of the invention wherein Y is O and X is O may be prepared asfollows:

Bromophenol A¹ ##STR57## is treated with a protecting compound such aschloro-t-butyldimethylsilane, benzyl bromide or bromomethyl methylether, preferably benzyl bromide or bromomethyl methyl ether forortho-bromophenol, employing conventional procedures to form theprotected bromophenyl compound B¹ ##STR58## wherein Pro represents aprotecting group.

Examples of protecting compounds suitable for use herein in reactingwith bromophenol A¹ include those set out hereinbefore with respect toprotection of alcohol A.

Protected compound B¹ is then transmetallated (using a procedure similarto that set out above with respect to transmetallization of B usingn-butyllithium in THF) and condensed with hemiacetal C to form thecondensed 7-oxabicycloheptane compound XXII ##STR59##

The condensed compound XXII is then subjected to hydrogenolysis bytreatment with hydrogen in the presence of a catalyst such as palladiumon charcoal in acetic acid, to form the alcohol XXIII in the case wherePro is a silyl or methoxymethyl ether protecting group or to form XXIVdirectly when Pro is benzyl. ##STR60## When Pro is a silyl protectinggroup, compound XXIII is deprotected by treatment with, for example, asolution of acetonitrile and aqueous hydrofluoric acid to form thedeprotected alcohol XXIV ##STR61##

The alcohol XXIV is then alkylated by treating a solution of alcoholXXIV in tetrahydrofuran with a molar equivalent of sodium hydride or oneto four equivalents of a carbonate base such as potassium carbonate. Theresulting phenoxide solution is alkylated by treating with ahaloalkanoic acid ester F

    Hal--(CH.sub.2).sub.n --CO.sub.2 alkyl                     F

employing a molar ratio of F:XXIV of from about 1:1 to about 3:1, in thepresence of an inert organic solvent such as THF or dimethylformamide ordimethoxyethane, to form ester XXV ##STR62##

Alternatively, when the protecting group in XXIII is methoxymethyl, thefree hydroxyl is protected as a benzyl ether. The methoxymethylprotecting group is removed by treatment with aqueous acid. Theresulting phenol is alkylated with ethyl bromoacetate as described abovefor the alkylation of XXIV. The benzyl protecting group is then removedby hydrogenolysis with palladium hydroxide and hydrogen to give XXV.

Alternatively, alcohol ester starting materials of formula XXV may beprepared by following the procedure as described in U.S. Pat. No.4,536,513.

Next, the alcohol ester XXV is subjected to a Jones oxidation asdescribed hereinbefore with respect to the oxidation of alcohol IIIB, toform acid XXVI ##STR63##

The acid XXVI is then used to prepare compounds of the invention offormula IJ and IK using the procedures set out hereinbefore with respectto conversion of acid XIII to ester IH ##STR64##

Compounds of the invention wherein Y is a single bond or O and X is Smay be prepared starting with acid XIII or XXVI as follows:

Acid XIII or XXVI is reacted with oxalyl chloride, optionally in thepresence of catalytic amounts of dimethylformamide, in methylenechloride, to form the corresponding acid chloride which is amidated byreacting with ammonia to form the amide XXVII ##STR65##

Alternatively, acid XIII or XXVI is reacted with an alkylchloroformatein the presence of an amine such as triethylamine to form the mixedanhydride which is amidated by reacting with methanol-ammonia solutionor concentrated aqueous ammonia solution to form amide XXVII.

Amide XXVII is then treated with phosphorus pentasulfide (P₂ S₅) orLawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) toform the corresponding thioamide XXVIII ##STR66## which is treated withbromopyruvic acid ##STR67## in a polar solvent such as dimethylformamidein the presence of a weak base such as K₂ CO₃ employing a molar ratio ofXXVIII: bromopyruvic acid of within the range of from about 1:1 to about1:1.5 to form thiazoline XXIX ##STR68##

Thiazoline XXIX is then dehydrated by treatment with a sulfonyl chloridesuch as methanesulfonyl chloride in the presence of a base such astriethylamine to form thiazole acid XXX ##STR69## which is then made toundergo a carbodiimide coupling reaction with amine ##STR70## in thepresence of DCC or WSC under an inert atmosphere such as argon employinga molar ratio of E:XXX of within the range of from about 1:1 to about2:1, to form amide IL ##STR71##

Alternatively, acid XXX can be activated by conversion to thecorresponding acid chloride by treating acid XXX with oxalyl chloride ina non-polar solvent such as benzene. The acid chloride is then coupledwith amine E using an amine base such as triethylamine or pyridine toform IL.

Compounds of the invention where Y is a single bond or O and X is NH areprepared starting with acid XIII or XXVI which is made to undergo acoupling reaction with amine G ##STR72## where BOC is t-butyloxycarbonyland Pro is a protecting group such as benzyl, in the presence of acoupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (WSC) and 1-hydroxybenzotriazole (HOBT) and methylenechloride employing a molar ratio of XIII or XXVI:G of within the rangeof from about 1.2:1 to about 1:1, for a period of from about 12 to about90 hours. The resulting amide is made to undergo a thionation reactionby treating the amide with Lawesson's reagent in the presence of benzeneat a temperature of from about 50° to about 75° C. for a period of fromabout 1 to about 4 hours, to form the ester XXXI ##STR73## The esterXXXI is cyclized by treating a solution of XXXI in an inert solvent suchas acetonitrile, chloroform or tetrahydrofuran with triphenylphosphine(employing a molar ratio of XXXI:triphenylphosphine of from about 0.8:1to about 1:1) and carbon tetrachloride in the presence of an amine basesuch as triethylamine or diisopropylethylamine, to form imidazolineXXXII ##STR74## Imidazoline XXXII is then deprotected to remove the Proprotecting group, using conventional procedures for example, byhydrogenation when Pro is benzyl, to form the acid XXXIII ##STR75##Next, the acid XXXIII is made to undergo a coupling reaction with amineE in the presence of an amine base such as pyridine or triethylamineunder an inert atmosphere such as argon in the presence of a couplingagent such as WSC and HOBT and chloroform, employing a molar ratio ofE:XXXIII of within the range of from about 0.8:1 to about 1.2:1 to formamide XXXIV ##STR76## The amine XXXIV in solution in methylene chlorideis then treated with trifluoroacetic acid to remove the BOC group andform amide XXXV ##STR77## Amide XXXV is oxidized by treatment with anoxidizing agent such as manganese dioxide in the presence of an inertsolvent such as chloroform to form ester IM ##STR78##

Compounds of the invention wherein n is O and Y is a single bond, thatis benzoic acids or derivatives thereof of the structure IN ##STR79##may be prepared starting with bromobenzyl alcohol A₂ ##STR80## which istreated with a protecting compound such as t-butylchlorodiphenylsilane,in the presence of 4-dimethylaminopyridine and an amine base such astriethylamine and an inert solvent, such as methylene chloride,employing conventional procedures, to form the protected bromobenzylcompound B² ##STR81## wherein Pro represents a protecting group.

Examples of protecting compounds suitable for use herein with theexclusion of benzyl bromide are as set out hereinbefore in reacting withbromophenalkyl alcohol A.

The protected compound B² is then transmetallated by treatment with t-C₄H₉ Li or n-C₄ H₉ Li in the presence of diethyl ether or tetrahydrofuranat reduced temperature of from about -100° to about 0° C. (or issubjected to a Grignard reaction by treatment with magnesium in thepresence of an inert organic solvent such as tetrahydrofuran (THF) ordiethyl ether) and then is condensed with(exo)octahydro-5,8-epoxy-1H-benzopyran-3-ol or(exo)octahydro-4,7-epoxyisobenzofuran-1-ol (prepared as described inU.S. Pat. No. 4,143,054) of the structure C ##STR82## employing a molarratio of C:B² of within the range of from about 1:2 to about 1:4, in thepresence of an inert organic solvent such as THF at a reducedtemperature of from about -78° to about 25° C., to form the condensed7-oxabicycloheptane compound IIA ##STR83##

Compound IIA is then protected by treatment with, for example, asolution of acetic anhydride and pyridine in the presence of4-dimethylaminopyridine to form compound XIA ##STR84##

The protected alcohol XIA is then deprotected using conventionalprocedures and the resulting alcohol subjected to a Jones oxidationemploying procedures described hereinbefore to form crude acid. Thecrude acid is deacetylated by reaction with aqueous hydroxide in thepresence of inert organic solvent such as THF and then esterified, forexample, by treatment with diazoalkane, such as diazomethane, or acidicalcohol, to form the alcohol ester XIIA ##STR85##

The alcohol ester is then subjected to hydrogenolysis as described aboveto provide alcohol ester compound XIIB ##STR86##

Next, the alcohol ester XIIB is subjected to a Jones oxidation to formthe acid XIIIA ##STR87##

In a preferred method, compounds of the invention wherein n is 0, m is 1and Y is a single bond, and R is in the ortho position, that is benzoicacids or derivatives thereof of the structure INa ##STR88## may beprepared starting with oxazoline B³ ##STR89## (prepared as described byA. I. Meyers et al in J. Org. Chem. 39, 2787 (1974)) which is metallatedby treatment with t-C₄ H₉ Li or n-C₄ H₉ Li in the presence of diethylether or tetrahydrofuran at reduced temperature of from about -100° C.to about 0° C. and then is condensed with(exo)octahydro-4,7-epoxyisobenzofuran-1-ol (prepared as described inU.S. Pat. No. 4,143,054) of the structure Ca ##STR90## employing a molarratio of Ca:B³ of within the range of from about 1:2 to about 1:4, inthe presence of an inert organic solvent such as THF at a reducedtemperature of from about -78° to about 0° C., to form the condensed7-oxabicycloheptane compound IIA' ##STR91##

Compound IIA' is then subjected to aqueous acidic hydrolysis bytreatment with aqueous oxalic acid to form compound XIA' ##STR92## XIA'is then subjected to hydrogenolysis as described above andesterification to provide alcohol ester compound XIIB' ##STR93##

Compound XIIB' may be used in place of XIIB to form acid XIIIA'##STR94##

The acid XIIIA or XIIIA' is then used in place of acid XIII to form thecorresponding benzoic acids of structure IO ##STR95## including##STR96##

Compounds of formula I wherein Z is ##STR97## and Y is --CH═CH-- may beprepared starting with alcohol XII wherein n is 2 which is treated witha silane protecting compound as described hereinbefore in the presenceof an amine base, such as triethylamine and an inert solvent such asmethylene chloride and N,N-dimethylaminopyridine (DMAP) to form theprotected alcohol XIIa. ##STR98## The protected alcohol XIIa is thentreated with lithium diisopropylamide in the form of a cooled (-78° to0° C.) mixture of diisopropylamine and t-butyllithium or n-butyllithium,under argon. The resulting mixture is treated with diphenyl diselenideat a temperature of within the range of from about -78° to about 25° C.,to form the corresponding selenide ##STR99## Selenide XIIb in an inertorganic solvent such as ethyl acetate and/or methanol is treated with anoxidizing agent such as aqueous hydrogen peroxide to form the cinnamateXIIc ##STR100## The protecting group is removed from XIIc by treatingXIIc with acetyl chloride in the presence of an organic solvent such asmethanol to form the alcohol XIId ##STR101## Alcohol XIId may then beemployed to form compounds of formula I wherein Z is ##STR102##employing procedures described hereinbefore.

Compounds of formula I_(x) may be prepared by treating a compound offormula I wherein X is O, R² is H, Z is ##STR103## and R is CO₂ H with aprotecting compound such as benzyl bromide in the presence of base suchas potassium carbonate or sodium hydride and an inert organic solventsuch as dimethylformamide to form the protected compound I_(xa)##STR104## causing I_(xa) to undergo an oxidative rearrangement bytreating I_(xa) with sodium nitrite in the presence of organic acid suchas acetic acid and acetic anhydride, or nitrogen tetroxide or nitrosylchloride, and a solvent such as dioxane at temperatures of from about85° to about 105° C., to form the corresponding ester I_(xb) ##STR105##and removing the protecting group by hydrogenation in the presence of ahydrogenation catalysis such as palladium on charcoal to form I_(x).

The starting bromophenylalkyl alcohol A where n is 2 may be prepared bysubjecting aldehyde M ##STR106## to a Wittig reaction with (C₆ H₅)₃PCHCO₂ CH₃ to form the ester N ##STR107## which is made to undergo adouble bond reduction by treatment with hydrogen in the presence ofrhodium on alumina catalyst in the presence of methanol to form ester O##STR108## Ester O is then reduced by treatment with diisobutylaluminumhydride in the presence of toluene solvent to form alcohol A.

The compounds of formula I of the invention wherein Z is --CH═CH or--(C₂)₂ -- may be prepared as follows.

Compounds of the invention where Z is --CH═CH-- and preferably in thecis form, and X is O are prepared starting with the hydroxymethylcompound AA ##STR109## (which is prepared as described in U.S. Pat. No.4,143,054) which is subjected to a Jones oxidation wherein AA is reactedwith Jones' Reagent (CrO₃ dissolved or suspended in aqueous sulfuricacid, prepared as described in Fieser & Fieser, "Reagents for OrganicSynthesis", Vol I, p. 142 (1967)) in the presence of acetone, under aninert atmosphere such as argon at a temperature within the range of fromabout -10° to about 20° C., to form the corresponding carboxylic acid BB##STR110##

Acid BB, in an inert organic solvent, such as tetrahydrofuran, is thenmade to undergo a carbodiimide coupling reaction with amide Da##STR111## in the presence of dicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) and1-hydroxybenzotriazole under an inert atmosphere such as argon employinga molar ratio of Da:BB of within the range of from about 1.2:1 to about1:1, to form hydroxybisamide IIa ##STR112##

Hydroxybisamide IIa is then subjected to cyclodehydration wherein asolution of IIa in an inert organic solvent such as tetrahydrofuran,acetonitrile or chloroform, under an inert atmosphere such as argon, istreated with triphenylphosphine and carbon tetrachloride in the presenceof an amine base such as triethylamine, to form oxazoline IIIa.##STR113##

Alternatively, hydroxybisamide IIa is treated with a sulfonyl chloride,such as methane sulfonyl chloride, and an amine base such astriethylamine followed by treatment with potassium carbonate in acetoneto form oxazoline IIIa.

Oxazoline IIIa is oxidized by treatment with manganese dioxide or nickelperoxide preferably nickel peroxide to form the oxazole IDa ##STR114##

Alternatively, oxazole IDa can be prepared from acid BB ##STR115## by acarbodiimide coupling as described previously except substituting CCafor Da to obtain IIb. ##STR116## where Pro is a conventional protectinggroup. Hydroxyamide IIb is then subjected to a cyclodehydration andoxidation as described for IIa and IIIa to form ID' ##STR117## Theprotecting group of ID' can be removed to form the corresponding acidID" which is treated with excess ##STR118## oxalyl chloride in thepresence of an inert organic solvent such as toluene, methylenechloride, or chloroform, and optionally a catalytic amount ofdimethylformamide, while stirring under an inert atmosphere such asargon, to form the crude acid chloride IDa" ##STR119## which is treatedwith amine hydrochloride E' ##STR120## in the presence of an organicbase such as triethylamine under an inert atmosphere such as argon,employing a molar ratio of IDa":E' of within the range of from about0.5:1 to about 2:1 and preferably from about 0.8:1 to about 1:1, to formIDa"'. ##STR121##

Compounds of formula I wherein Z represents --CH═CH-- which is the transdouble bond isomer may be prepared starting with hydroxymethyl compoundAA which includes a cis double bond. Compound AA is treated with aprotecting compound such as t-butyldimethylsilyl chloride or other silylprotecting group as described hereinbefore in the presence of imidazoleor triethylamine and an inert organic solvent such as methylene chlorideor tetrahydrofuran, to form the protected compound AA' ##STR122## Asolution of the protected alcohol in an inert organic solvent such asmethylene chloride or acetone is treated with excess ozone at reducedtemperature of from about -78° to about -60° C. followed by treatmentwith dimethyl sulfide (molar ratio of AA':(CH₃)₂ S of within the rangeof from about 0.01:1 to about 0.2:1), to form the aldehyde AA²##STR123##

Aldehyde AA₂ is then treated with a mixture of lithium bromide orlithium chloride and trimethylphosphonoacetate and triethylamine in aninert organic solvent such as methylene chloride or chloroform to formthe ester AA₃ ##STR124##

A solution of ester AA₃ in an inert organic solvent such astetrahydrofuran, diethyl ether or dimethyoxyethane is cooled to atemperature of from about -78° to 0° C. and reacted withdiisobutylaluminum hydride in an aromatic solvent such as toluene for aperiod of from about 0.5 to about 4 hours to form alcohol AA₄ ##STR125##

Alcohol AA₄ is treated with bromotriphenylphosphonium bromide (formed byadding bromine to triphenylphosphine in toluene or other aromaticsolvent under an inert atmosphere such as argon, at a reducedtemperature of from about -10° to about 10° C.) in the presence ofpyridine and toluene, at a reduced temperature of from about -10° toabout 10° C., to form bromide AA₅ ##STR126##

An acetic acid ester such as t-butyl acetate or ethyl acetate is treatedwith a solution of LDA (lithium diisopropylamide) in an inert organicsolvent such as tetrahydrofuran and at a reduced temperature of fromabout -78° to about -60° C. for a period of from about 0.5 to about 2hours followed by addition of a solution of bromide AA₅ in an inertsolvent such as tetrahydrofuran to form ester AA⁶ (n is 2) ##STR127##

For compounds of the invention where Z═--CH═CH-- in the trans form and nis 1, 3, or 4, aldehyde XI is allowed to react with a phosphonium saltof formula P ##STR128## in the presence of a strong base such aspotassium t-amylate in toluene or NaH/dimethylsulfoxide to give XIII'##STR129## which is oxidized and esterified using procedures known tothose skilled in the art to form ester AA⁶ (where n=1, 3, and 4).

Ester AA⁶ is then deprotected by treating AA⁶ in methanol under an inertatmosphere such as argon with hydrochloric acid in methanol (prepared byadding acetyl chloride to methanol) to form alcohol AA⁷ ##STR130##

AA⁷ may then be used in place of AA as a starting material following theprocedure hereinbefore described to form acid AA⁸ ##STR131## andsubsequently to form the trans compound of formula IDaa of the invention##STR132##

Compounds of the invention IB wherein Z is --CH═CH-- and X is S may beprepared starting with acid BB or AA⁸ as follows:

Acid BB or is reacted with oxalyl chloride, optionally in the presenceof catalytic amounts of dimethylformamide, in methylene chloride, toform the corresponding acid chloride which is amidated by reacting withammonia to form the amide XXXVII ##STR133##

Alternatively, acid BB or AA⁸ is reacted with an alkylchloroformate inthe presence of an amine such as triethylamine to form the mixedanhydride which is amidated by reacting with methanol-ammonia solutionor concentrated aqueous ammonia solution to form amide XXXVII.

Amide XXXVII is then treated with phosphorus pentasulfide (P₂ S₅) orLawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) toform the corresponding thioamide XXXVIII ##STR134## which is treatedwith bromopyruvic acid ##STR135## in a polar solvent such asdimethylformamide in the presence of a weak base such as K₂ CO₃employing a molar ratio of XXXVIII: bromopyruvic acid of within therange of from about 1:1 to about 1:1.5 to form thiazoline XXXIX##STR136##

Thiazoline XXXIX is then dehydrated by treatment with a sulfonylchloride such as methanesulfonyl chloride in the presence of a base suchas triethylamine to form thiazole acid XL ##STR137## which is then madeto undergo a carbodiimide coupling reaction with amine ##STR138## in thepresence of DCC or WSC under an inert atmosphere such as argon employinga molar ratio of A"':XL of within the range of from about 1:1 to about2:1, to form amide IF_(a) ##STR139##

Compounds of the invention IE where X is NH and Z¹ is --CH═CH-- areprepared starting with acid BB or AA⁸ which is made to undergo acoupling reaction with amine O ##STR140## where Boc ist-butyloxycarbonyl and Pro is a protecting group such as preferably--CH₂ CH₂ Si(CH₃)₃, in the presence of a coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) and1-hydroxybenzotriazole (HOBT) and methylene chloride employing a molarratio of BB or AA⁸ :Q of within the range of from about 1.2:1 to about1:1, for a period of from about 12 to about 90 hours. The resultingamide is made to undergo a thionation reaction by treating the amidewith Lawesson's reagent in the presence of benzene at a temperature offrom about 50° to about 75° C. for a period of from about 1 to about 4hours, to form the ester XLI ##STR141## The ester XLI is cyclized bytreating a solution of XLI in an inert solvent such as acetonitrile,chloroform or tetrahydrofuran, with triphenylphosphine (employing amolar ratio of XLI:triphenylphosphine of from about 0.8:1 to about 1:1)and carbon tetrachloride in the presence of an amine base such astriethylamine or diisopropylethylamine, to form imidazoline XLII##STR142## Imidazoline XLII is then deprotected to remove the Proprotecting group, using conventional procedures, for example, bytreatment with trifluoroacetic acid in the presence of methylenechloride, to form the acid XLIII ##STR143## Next, the acid XLIII is madeto undergo a coupling reaction with amine A"' in the presence of anamine base such as pyridine or triethylamine under an inert atmospheresuch as argon in the presence of a coupling agent such as WSC and HOBTand chloroform, employing a molar ratio of A"':XLIII of within the rangeof from about 0.8:1 to about 1.2:1 to form amide XLIV ##STR144## AmideXLIV is oxidized by treatment with an oxidizing agent such as manganesedioxide in the presence of an inert solvent such as chloroform to formester IFb ##STR145##

The aforementioned esters of the invention may be converted to thecorresponding acids, that is IS ##STR146## by treating the esters with abase, such as lithium hydroxide, sodium hydroxide or potassium hydroxideto form the corresponding alkali metal salt, followed by neutralizationwith an acid, such as dilute hydrochloric acid or oxalic acid to formthe acid compounds of the invention.

Compounds of formula I wherein Z is --(CH₂)₂ -- may be prepared fromacid IGa by subjecting IGa to hydrogenation using, for example, ahydrogenation catalyst, such as palladium on carbon, in an inert organicsolvent such as ethyl acetate (EtOAc) or acetic acid (AcOH) to form acidof the invention IGa' ##STR147##

Compounds of the invention wherein R is CONHSO₂ R³, that is IT##STR148## are prepared by treating acid IS, IGa or IGa' with asulfonamide of the structure H ##STR149## in the presence of a couplingagent such as carbonyldiimidazole or WSC in the presence of an aminesuch as dimethylaminopyridine under an inert atmosphere such as argonemploying a molar ratio of H:IS or IG, or IGa' of within the range offrom about 0.8:1 to about 1.2:1, to form sulfonamide IT.

Acids IS, IGa and IGa' may be converted to the corresponding alkylesters by treating the acids IS, IGa and IGa' with the appropriatealcohol under acid catalysis to form the esters.

Compounds of the invention wherein R is --CH₂ -5-tetrazolyl, Z is##STR150## and Y is a single bond, or Z is --(CH₂)₂ -- that is IU whereY is a single bond ##STR151## where Z' is ##STR152## or --(CH₂)₂ -- areprepared by subjecting esters IH, IJ, IL, IM, IP, IMa, IQ or IR or theesters of IS, IGa or IGa' where Z is ##STR153## or --(CH₂)₂ -- toreduction with a hydride reagent such as lithium borohydride or sodiumborohydride to afford alcohol XXXVIIA ##STR154## which is converted tothe bromide on treatment with triphenylphosphonium dibromide in an inertsolvent such as toluene. The bromide is then converted to nitrileXXXVIIIA on treatment with an alkali metal cyanide in a polar solventsuch as methanol/water. ##STR155##

The nitrile XXXVIIIA is then subjected to a cycloaddition reaction bytreating XXXVIIIA with sodium azide in the presence of ammoniumchloride, dimethylformamide and lithium chloride at a temperature offrom about 100° C. to about 130° C. to form IU.

Compounds of the invention wherein R is --CH₂ --5-tetrazolyl and Y=O,that is IU where Y is O, are prepared by conversion of alcohol XXIII toether XXXIXA using the procedures set out hereinbefore for theconversion of XII to esters IE, IH and IJ ##STR156## which are convertedto the corresponding nitrile by deprotection, for example with aqueousHF, followed by alkylation with halonitrile J in the

    X--(CH.sub.2).sub.n --CN                                   J

presence of a base such as sodium hydride or potassium carbonate.

The nitrile is then subjected to a cycloaddition reaction by treatingwith sodium azide in the presence of ammonium chloride,dimethylformamide and lithium chloride at temperatures from about 100°C. to about 130° C. to form IU.

Compounds of the invention wherein R is --CH₂ --5-tetrazolyl, that isIJa ##STR157## are prepared by treating alcohol Ka (prepared asdescribed in U.S. Pat. No. 4,654,356) ##STR158## with a Wittig reagentof the structure La ##STR159## in the presence of a base, such aspotassium t-butoxide or sodium hydride-dimethyl sulfoxide employing amolar ratio of Ka:La of within the range of from about 1:1 to about0.2:1 to form the hydroxymethyl compound XIIa ##STR160## which istreated with protecting compound Ma

    Pro-Halide                                                 Ma

for example, bromomethyl methyl ether to form the protected tetrazoleXIIIa ##STR161##

The protected tetrazole XIa may then be used in place of hydroxymethylcompound AA to form the various compounds of the formula XIVa wherein Xis O, S or NH ##STR162## which is deprotected by treatment with aqueousacid such as aqueous hydrochloric acid to form compounds of theinvention IJa.

Compounds of formula I wherein R is CONHR^(3a) wherein R^(3a) is otherthan H may be prepared from the corresponding acid ##STR163## bytreating acid I₁ with WSC in the presence of dimethylformamide and HOBT,organic basic such as triethylamine and amine E"

    HNHR.sup.3a                                                E"

to form the amide of the invention I₂ ##STR164## where R^(3a) is loweralkyl, aryl or aralkyl.

Compounds of formula I wherein R is CONH₂ may be prepared from thecorresponding acid I₁, employing the procedure as described above formaking amide I₂ except that ammonium chloride is employed in place ofamine E" to form the amide of the invention I₃ ##STR165##

Compounds of formula I wherein R is CH₂ OH may be prepared from thecorresponding ester I₄ ##STR166## which is treated with a reducing agentsuch as lithium borohydride (LiBH₄) in the presence of diethyl ether andtetrahydrofuran to form the alcohol I₅ ##STR167##

The compounds of this invention have four centers of asymmetry asindicated by the asterisks in formula I. However, it will be apparentthat each of the formulae set out above which do not include asterisksstill represent all of the possible stereoisomers thereof. All of thevarious stereoisomeric forms are within the scope of the invention.

The various stereoisomeric forms of the compounds of the invention,namely, cis-exo, cisendo and all trans forms and stereoisomeric pairsmay be prepared by employing starting materials and following theprocedures as outlined in U.S. Pat. No. 4,143,054. Examples of suchstereoisomers are set out below. ##STR168##

The nucleus in each of the compounds of the invention is depicted as##STR169## for matter of convenience; it will also be appreciated thatthe nucleus in the compounds of the invention may be depicted as##STR170##

The compounds of this invention are thromboxane receptor antagonists andas such are useful as inhibitors of thromboxane receptor mediatedactions. The term "thromboxane receptor antagonist" includes compoundswhich are so-called thromboxane A² receptor antagonists, thromboxane A²antagonists, thromboxane A² /prostaglandin endoperoxide antagonists,TP-receptor antagonists, or thromboxane antagonists.

The compounds of the invention are also thromboxane synthetaseinhibitors and thus are useful as inhibitors of thromboxane production.

The compounds of this invention are useful as inhibitors of plateletfunction, i.e., for the prevention and treatment of thrombotic vascularocclusive disorders, whether complete or partial, for example, arterialthrombosis, including that of the coronary, cerebral, ophthalmic,hepatic, mesenteric, renal, peripheral arteries or vascular or organgrafts, unstable angina, transient ischemic attacks, or intermittentclaudication. They may be useful to prevent thrombosis followingvascular injury produced in the course of diagnostic or therapeuticprocedures such as endarterectomy or angiography. The compounds may beuseful in the treatment or prevention of disorders characterized byplatelet consumption and/or activation, including, platelet activation,dysfunction, and/or loss during extracorporeal circulation, the use ofradiographic contrast agents, thrombotic thrombocytopenia purpura,disseminated intravascular coagulation, purpura fulminans, hemolytictransfusion reaction, or hemolytic uremic syndrome, systemic lupus,cyclosporine-induced renal toxicity, pulmonary hypertension, sideeffects from dialysis, or abdominal aortic aneurism repair. Thecompounds may be used in the treatment of venous thrombosis or embolism,including pulmonary embolism, deep venous thrombosis, hepatic veinthrombosis, and renal vein thrombosis.

The compounds of this invention are useful as inhibitors of arterial orvenous vasoconstriction. Accordingly, they may be useful to preventvasoconstriction associated with unstable angina, chronic stable angina,and variant, or Prinzmetal's angina, Raynaud's syndrome, migraineheadache, vasospasm of the coronary, cerebral, ophthalmic, hepatic,mesenteric, renal, peripheral arteries or vascular grafts, vascularinjury such as that associated with surgery or trauma. Hypertension ofpregnancy, the hepato-renal syndrome, and pulmonary hypertension areadditional examples of vasoconstrictive disorders treatable by thecompounds of this invention.

The compounds of this invention are useful as inhibitors ofbronchoconstriction, i.e., airway hyperresponsiveness, allergicbronchospasm, asthma, and bronchoconstrictive responses toenvironmental, infectious, noxious or mechanical stimuli.

The compounds of this invention are useful as inhibitors of ischemic andreperfusion injury to various tissues, including, myocardium, skin,brain, bowel, or kidney, alone or in combination with other agentsintended to restore blood flow. For example, these compounds may beuseful for improving postischemic myocardial function and decreasingmyocardial infarct size. Ischemia caused by reduced blood flow duringdiagnostic or therapeutic procedures may benefit by treatment with thesecompounds, for example, they reduce the myocardial stunning observedafter bypass surgery. In addition, they may be useful for reducing thetissue injury caused by a stroke.

The compounds of this invention may be useful in the prevention ortreatment of other conditions including burns, diabetic retinopathy,tumor metastases and tardive dyskinesia. The compounds may be useful inpotentiating diuretic-induced diuresis.

In addition, the thromboxane receptor antagonists of the invention maybe used with a thrombolytic agent such as t-PA, streptokinase,urokinase, prourokinase or anisoylated plasminogenstreptokinaseactivator complex (APSAC) within 6 hours of a myocardial infarction. Insuch case, the thrombolytic agent may be used in amounts conventionallyemployed, for example, as disclosed in the Physicians' Desk Referencefor reducing post-ischemic myocardial injury.

The compounds of the invention can be administered orally orparenterally to various mammalian species known to be subject to suchmaladies, e.g., humans, cats, dogs and the like in an effective amountwithin the dosage range of about 0.1 to about 100 mg/kg, preferablyabout 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25mg/kg (or from about 1 to about 2500 mg, preferably from about 5 toabout 2000 mg) on a regimen in single or 2 to 4 divided daily doses.

The oxazole derivatives of the invention, that is compounds of formula Iwhere X is O have particularly long duration of action and these may, ifdesired, be administered in the above dosages once daily, once everyother day, or if desired once daily two times a week.

The active substance can be utilized in a composition such as tablet,capsule, solution or suspension containing about 5 to about 500 mg perunit of dosage of a compound or mixture of compounds of formula I or intopical form for wound healing (0.01 to 5% by weight compound of formulaI, 1 to 5 treatments per day). They may be compounded in conventionalmatter with a physiologically acceptable vehicle or carrier, excipient,binder, preservative, stabilizer, flavor, etc., or with a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene) ascalled for by accepted pharmaceutical practice. Also as indicated in thediscussion above, certain members additionally serve as intermediatesfor other members of the group.

The compounds of the invention may also be administered topically totreat peripheral vascular diseases and as such may be formulated as acream or ointment.

The following Examples represent preferred embodiments of the presentinvention. Unless otherwise indicated, all temperatures are expressed indegrees Centigrade.

EXAMPLE 1[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A. 3-(2-Bromophenyl)-2-propenoic acid, methyl ester

To a stirred solution of 161.2 g (871 mmol) of 2-bromobenzaldehyde in700 mL of dry THF (distilled from potassium/benzophenone) at roomtemperature under argon, was added 298.4 g (892 mmol, 1.024 equiv) ofmethyl(triphenylphosphoranylidene)acetate (Aldrich) over 1 hour in 20 gportions. Reaction was mildly exothermic and the mixture becamehomogeneous. The resulting solution was stirred for 18 hours duringwhich some precipitate formed. Addition of 200 mL hexane caused furtherprecipitation. Filtration was followed by evaporation. The residue wasslurried with a large volume of hexane (more precipitation) andrefrigerated overnight. This was filtered, and the filtrate was passedthrough a plug of silica gel (approximately 1 kg) eluting with 10% ethylacetate (EtOAc) in hexane. The eluant was concentrated in vacuo to give201.5 g of a colorless oil. This oil was pure title compound as a 4:1mixture of double bond isomers (trans predominating). The yield of titlecompound was 96%.

    ______________________________________                                        TLC (silica gel, 5% EtOAc in hexane - I.sub.2):                               ______________________________________                                        2-bromobenzaldehyde                                                                              0.29                                                       title compound     0.20                                                       ______________________________________                                    

B. 2-Bromobenzenepropanoic acid, methyl ester

A mixture of 201.5 g (836 mmol) of Part A acrylate and 8.4 g of 5%rhodium on alumina catalyst (MCB) in 1.0 L of methanol was stirred atroom temperature under an atmosphere of hydrogen (balloon) for in excessof 8 hours. ¹ H NMR analysis of an aliquot showed about a 1:1 mixture oftitle compound and trans Part A compound with no cis Part A compound.The mixture was diluted with 500 mL additional methanol (MeOH) and 12.6g more catalyst was added. After hydrogenation overnight the reactionwas complete. The reaction mixture was passed through Celite and aMillipore/Fluropore membrane filter (0.5 μm FH) with a prefilter pad,and the filtrate was concentrated in vacuo to obtain two immiscibleoils. One of the oils was water soluble and gave a highly acid, i.e.aqueous solution. Solid NaHCO₃ and Na₂ SO₄ were carefully added (gas wasevolved). The mixture was diluted with CH₂ Cl₂, filtered, and evaporated(and re-evaporated with CH₂ Cl₂ to drive off MeOH) to obtain 196.9 g ofclear oil. This oil was 95% pure title compound with 5% of debromo titlecompound. The corrected yield of title compound was 92% (187.1 g).

    ______________________________________                                        TLC (silica gel, 15% EtOAc in hexane - UV):                                   ______________________________________                                        Part A compound        0.36                                                   (much more strongly UV absorbing)                                             title compound         0.40                                                   ______________________________________                                    

C. 2-Bromobenzenepropanol

To a stirring solution of 196.9 g (95% pure=187.1 g, 770 mmol) of Part Bcompound in 770 mL of toluene under argon cooled to 0° (ice bath), wasadded over 45 minutes 830 mL of 1.0M diisobutylaluminum hydride(DIBAl-H) in toluene solution (830 mmol, Aldrich). The reaction was notvery exothermic. After the mixture was stirred for 1 hour, TLC indicatedapproximately half of the starting material remained. Next, 580 mL of1.5M DIBAl-H in toluene solution (870 mmol, Aldrich) was added slowly.The ice bath was removed and stirring was continued for 2 hours. Themixture was then poured slowly into 1.2 L of 6M aqueous HCl stirring inan ice bath. This quench was exothermic and gas was evolved. After themixture was recooled to 0°, the layers were separated, and the organiclayer was washed with 1M aqueous HCl and brine. It was then dried overNa₂ SO₄ and MgSO₄ and evaporated (and re-evaporated with CH₂ Cl₂ todrive off toluene) to obtain 173.0 g of clear, colorless oil. This oilwas 95% pure title compound with 5% of debromo- title compound. Thecorrected yield of title compound was 99% (164.3 g).

    ______________________________________                                        TLC (silica gel, 15% EtOAc in hexane - anisaldehyde,                          UV):                                                                          ______________________________________                                        Part B compound  0.49                                                         (faintly staining)                                                            Title compound   0.11                                                         ______________________________________                                    

D. [3-(2-Bromophenyl)propoxy]dimethyl-(1,1,2-trimethylpropyl)silane

To a stirring solution of 173.0 g (95% pure=164.3 g, 764 mmol) of Part Ccompound and 57.8 g of imidazole (850 mmol) in 1.0 L of CHCl₃ at roomtemperature was added slowly 136.6 g (764 mmol) ofthexyldimethylchlorosilane. The reaction was mildly exothermic and aprecipitate formed. After stirring overnight, ¹ H NMR analysis of analiquot showed a trace of Part C compound remaining. Additionalthexyldimethylchlorosilane (6.8 g, 38 mmol, 0.05 equiv) was added. After2 days the mixture was evaporated. The residue was diluted with hexaneand filtered. The filtrate was evaporated and distilled (150°-180° at1.2 torr) to obtain 262.8 g of slightly cloudy, colorless oil. This oilwas 94% pure title compound with 5% of debromo-title compound. Thecorrected yield of title compound was 91% (247.0 g).

    ______________________________________                                        TLC (silica gel, 15% EtOAc in hexane anisaldehyde):                           ______________________________________                                        Part C compound  0.11                                                         Title compound   0.89                                                         ______________________________________                                    

E.Bromo[2-[3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]magnesium

A 2-L oven-dried flask containing a magnetic stir-bar was charged with19.0 g of hammer-crushed Mg turnings (782 mmol, Mallinckrodt) and placedunder an argon atmosphere. After 440 mL dry THF (distilled frompotassium/benzophenone) was added, the Mg was activated at roomtemperature by introduction of a crystal of iodine and 2 mL of1,2-dibromoethane (gas was evolved). This was followed by addition of207.4 g (94% pure=195.0 g, 546 mmol) of Part D compound in a singleportion. The reaction mixture briefly turned colorless, then amber. Theexothermic reaction brought the mixture to reflux. Additional dry THF(120 mL) was introduced to ensure product solubility on eventualcooling. Although the reaction was not violently exothermic, foamingmade it necessary to cool the mixture with a water bath. The water bathwas used intermittently until the exotherm subsided. The mixture wasthen heated to a gentle reflux for 1 hour and cooled to roomtemperature. No precipitate formed. The mixture consisted of a brown,clear solution of title compound and some unreacted Mg. This solutionwas used the same day to prepare title compound F as follows.

F.[1S-(1α,2α,3α,4α)]-α-[2-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol

A 5-L flask containing a magnetic stir-bar was charged with 63.1 g of3aR-(3aα,4β,7β,7aα)]-octahydro-4,7-epoxyisobenzofuran-1-ol (SQ 30,674)(405 mmol) and placed under an argon atmosphere. After 400 mL dry THF(distilled from potassium/benzophenone) was added, SQ 30,674 wasdissolved by stirring. The resulting solution was cooled to 0°, and bysyringe over 30 minutes, 192 mL of 2.0M C₂ H₅ MgBr (Aldrich, prewarmedto 30° to ensure homogeneity, 385 mmol, 0.95 equiv) was added. Gas wasevolved. After the addition was complete, stirring at 0° was continuedfor 1 hour. The solution of previously prepared Part E magnesiumcompound (546 mmol, 1.35 equiv theoretical) was introduced by cannulaover 1 hour. The temperature was maintained at 0° during the additionand for several hours afterward. A small amount of precipitate formed.The mixture was warmed to room temperature, and 50 mL dry THF was added.Some precipitate remained. This mixture was stirred for 6 days before290 mL of a saturated, aqueous solution of (83 g) NH₄ Cl was slowlyadded. The quench was slightly exothermic, the mixture warming itself toabout 40°. The mixture was stirred for 2 hours, and the inorganicsformed a white paste. To the mixture was added 1.0 L of CH₂ Cl₂. Theorganic supernatant was decanted from the paste. The paste was thenstirred with 500 mL CH₂ Cl₂. The organic layer was decanted, and thisprocedure was repeated. The combined organic layers were dried over 115g Na₂ SO₄ (total volume 3.5 L), and concentrated in vacuo. To drive offTHF the residue was re-concentrated after addition of 200 mL CH₂ Cl₂.This yielded 230 g of an oil. The oil was then quickly dissolved in 2.0L hexane. Crystallization began in minutes. The mixture was refrigeratedwith periodic agitation for 5 days. The crystals which formed werefiltered (cold) and washed with two 500 mL portions of refrigeratedhexane. After exposure to vacuum, 145.9 g of crystals (mp 99.5°-100.5° )were obtained. The crystals, pure, and a single diastereomer of Part Fcompound, represented an 83% yield. The mother liquors were evaporated,redissolved in 200 mL hexane, and placed in the freezer for 30 days. Asecond crop of crystals (8.7 g, pure, single diastereomer of Part Fcompound, 5% additional yield) was collected as above. (In an earlierrun, yields of the cospotting major and minor diastereomers were 94% and5% respectively. The minor diastereomer is an oil).

    ______________________________________                                        TLC (silica gel, 100% EtOAc - anisaldehyde):                                  ______________________________________                                        SQ 30,674        0.35                                                         Part F compound  0.78                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 141.8, 138.7, 129.5, 127.3, 126.2, 125.5,79.5, 77.3, 67.4, 62.2, 61.7, 51.7, 49.0, 34.2, 34.1, 29.7, 29.7, 28.0,25.2, 20.3, 18.5, -3.3.

G.[1S-(1α,2α,3α,4α)]-2-[[2-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-methanol

A mixture of 143.0 g (329 mmol) of Part F compound and 28.6 g of 20%palladium hydroxide on carbon catalyst (moist, <50% water, Aldrich) in2.0 L of glacial acetic acid was stirred rapidly under an atmosphere ofhydrogen (balloon) at room temperature for 30 hours. The reactionmixture was filtered through filter paper to remove most of thecatalyst. The filtrate was evaporated to 500 mL on a rotovapor in a 30°water bath under high vacuum. This was then passed through aMillipore/Fluropore membrane filter (0.5 μm FH) with a prefilter pad.Evaporation as above was followed by azeotropic removal of acetic acid(AcOH) with toluene (500 mL three times) and re-evaporation with CH₂ Cl₂to drive off toluene. The crude product, 144.9 g of an oil, consistedlargely of title compound (approximately 90%) with small amounts ofsolvent, the acetate of title compound (identical with Part H compound,less than 5%), and desilylated title compound (diol, less than 5%).

    ______________________________________                                        TLC (silica gel, 25% EtOAc in hexane - anisaldehyde):                         ______________________________________                                        Part F compound     0.07                                                      Title compound      0.16                                                      Part H compound     0.50                                                      desilylated title compound                                                                        0.00                                                      (diol)                                                                        ______________________________________                                    

    ______________________________________                                        TLC (silica gel, 100% EtOAc - anisaldehyde):                                  ______________________________________                                        Part F compound   0.82                                                        Title compound    0.85                                                        Part G compound   0.93                                                        desilylated G (diol)                                                                            0.20                                                        ______________________________________                                    

H.[1S-(1α,2α,3α,4α)]-2-[[2-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]methyl-7-oxabicyclo[2.2.1]hept-2-yl]heptane-3-methanol,acetate ester

A solution of 144.9 g (<329 mmol) of crude Part G compound in 200 mLpyridine (Burdick & Jackson) was stirred magnetically under argon atroom temperature while 50 mL (54 g, 530 mmol) of acetic anhydride wasadded in a single portion. The reaction mixture warmed to a peaktemperature of about 41° after 30 minutes. After 16 hours thehomogeneous mixture was rotoevaporated using a 70° water bath. Theresidue was coevaporated three times with toluene (500 mL). This gave163.5 g of an oil, crude title compound. The crude product containedtoluene, but no residual pyridine.

    ______________________________________                                        TLC (silica gel, 25% EtOAc in hexane - anisaldehyde):                         ______________________________________                                        Part G compound  0.20                                                         Part H compound  0.54                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 170.9, 140.4, 138.7, 129.6, 129.4, 126.2,125.9, 79.3, 79.2, 63.8, 62.4, 46.9, 46.0, 34.2, 34.0, 30.6, 29.5, 29.5,28.9, 25.1, 21.0, 20.4, 18.5, -3.4.

I.[1S-(1α,2α,3α,4α)]-2-[[3-[(Acetyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a stirring solution of 163.5 g of crude Part H compound in 2.0 Lacetone in a room temperature bath, was added slowly (over about 1 hourin 50 mL portions) 240 mL of Jones' Reagent with Mn⁺². Exothermicreaction brought the mixture to near reflux. As precipitate formedstirring became very difficult. The red color of the reagent persistedafter the last portion was introduced. The excess reagent was quenched30 minutes later by addition of 50 mL 2-propanol. The precipitated Crsalts were easily filtered. The salts were washed with acetone. Thefiltrate (2.4 L) was evaporated, and two immiscible oils were obtained.After addition of 500 mL CH₂ Cl₂, 100 mL brine, and 300 mL water,separation of the organic and aqueous layers was difficult. Introductionof 300 mL CHCl₃ allowed good separation. The aqueous layer wasre-extracted twice with 300 mL CHCl₃, and the combined extracts weredried over Na₂ SO₄ and evaporated in vacuo. This provided 164.5 g ofcrude title compound (containing desilylation by-product), a clear oil.

    ______________________________________                                        TLC [silica gel, 50% (5% CH.sub.3 COOH in ethyl acetate                       (EtOAc)) in hexane - anisaldehyde]:                                           ______________________________________                                        Part H compound  0.89                                                         Title compound   0.42                                                         ______________________________________                                    

J.[1S-(1α,2α,3α,4α)]-2-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A solution of 164.5 g of crude Part I compound in 1.0 L of acidicmethanol (prepared by cautious addition of 10 mL of acetyl chloride to1.0 L of methanol) was stirred under argon in a 2-L flask. TLC indicatedthat the reaction proceeded predominantly through one distinctintermediate. After 16 hours 30 g of NaHCO₃ was added cautiously over 10minutes. Neutralization was not exothermic, but gas was evolved. Themixture was stirred for 30 minutes before it was cautiously evaporated.The residue was diluted with 500 mL CH₂ Cl₂, dried over Na₂ SO₄, andfiltered. After the filtrate was evaporated, the crude product wascoevaporated in vacuo twice with toluene (60° bath, to remove some ofthe desilylation by-product). This gave 119.3 g of an oil. Crude titlecompound was judged to be roughly 75% pure with only about a third of anequivalent of desilylation by-product and a little diol (Part Gby-product).

    ______________________________________                                        TLC (silica gel, 50% (5% CH.sub.3 COOH in EtOAc) in                           hexane - anisaldehyde):                                                       ______________________________________                                        Part I compound  0.35                                                         intermediate     0.53                                                         title compound   0.31                                                         diol             0.11                                                         ______________________________________                                    

K.1S-(1α,2α,3α,4α)]-2-[(3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl)methyl]benzenepropanoicacid, methyl ester

To a stirring solution of 93.6 g 78% of the sample) of crude Part Jcompound in 1.5 L acetone in a room temperature bath, was added slowly(over about 1 hour in 50 mL portions) 150 mL of Jones' Reagent withMn⁺². (Jones' Reagent was prepared as described in Fieser & Fieser,"Reagents for Organic Synthesis", vol. 1, p. 142--Djerassi procedure.Into this Jones' Reagent was dissolved 1.0 g MnSO₄.H₂ O per L.).Exothermic reaction brought the mixture to near reflux. As precipitateformed stirring became very difficult. The red color of the reagentpersisted after the last portion was introduced. The excess reagent wasquenched 30 minutes later by addition of 50 mL 2-propanol. Theprecipitated Cr salts were easily filtered. The salts were washed withacetone. The filtrate was evaporated, and two immiscible oils wereobtained. After addition of 500 mL CHCl₃, 100 mL brine, and 300 mLwater, separation of the organic and aqueous layers was uncomplicated.The aqueous layer was re-extracted twice with 250 mL CHCl₃, and thecombined extracts were dried over Na₂ SO₄ and evaporated. This provided109.6 g of crude title acid, a pale green, clear oil. A portion (30.6 g,28% of the sample) of the crude title acid was flash chromatographed(1.0 kg Merck silica gel, 40% to 100% (5%CH₃ COOH in EtOAc) in hexanegradient). This provided 18.2 g of pure title acid as a viscous oil.Also isolated was 1.4 g of the diacid corresponding to title acid, asolid. The overall yields from Part F compound were 80% and 6%,respectively.

    ______________________________________                                        TLC (silica gel, 50% (5% CH.sub.3 COOH in EtOAc) in                           Hexane - anisaldehyde):                                                       ______________________________________                                        Part J compound  0.33                                                         diol             0.12                                                         title acid       0.31                                                         diacid           0.13                                                         ______________________________________                                    

L. N-(Cyclohexylbutyl)-L-serinamide

To a solution of 14.3 g of 4-cyclohexylbutylamine hydrochloride (74.7mmol), 16.1 g t-butoxycarbonyl (BOC)-(L)-serine (78.4 mmol, 1.05 equiv),10.1 g 1-hydroxybenzotriazole hydrate (74.7 mmol, 1.00 equiv), and 7.9 gN-methylmorpholine (78.4 mmol, 1.05 equiv) in 200 mL N,N-dimethylformamide (DMF) (Burdick & Jackson) stirring under argon at 0°, wasadded 15.0 g WSC (78.4 mmol, 1.05 equiv) in a single portion. All of theWSC dissolved. The reaction mixture was allowed to slowly warm to roomtemperature overnight, and a precipitate formed. The mixture wasrotoevaporated (60° bath) to 90 g of oil plus solid. This was dilutedwith 400 mL EtOAc and washed with 200 mL 0.3M aqueous HCl twice (allsolids dissolved at this point), then 200 mL 1.0M aqueous NaHCO₃ twice.To the organic layer was added 500 mL toluene, and this was dried overNa₂ SO₄ and evaporated. After coevaporation with toluene, 28.4 g of athick solidifying oil was obtained. This material, BOC-title compound,was dissolved in 150 mL CH₂ Cl₂, and while stirring at room temperatureunder argon, 100 mL trifluoroacetic acid was added (gas was evolved).After 4 hours the solvent was evaporated, and after coevaporation withCHCl₃, the crude product was flash chromatographed (1.0 kg silica gel,10% (10% conc. aq. NH₃ in CH₃ OH) in CH₂ Cl₂) to obtain 13.4 g of 95%pure title compound as a white solid. The corrected yield of titlecompound was 70% (12.7 g) overall from 4-cyclohexylbutylaminehydrochloride.

    ______________________________________                                        TLC (silica gel, 10% (10% conc. aq. NH.sub.3 in CH.sub.3 OH) in               CH.sub.2 Cl.sub.2 - anisaldehyde):                                            ______________________________________                                        4-Cyclohexylbutylamine                                                                           0.27                                                       BOC-title compound 0.43                                                       title compound     0.17                                                       ______________________________________                                    

M.[1S-(1α,2α,3α(R*),4α)]-2-[[3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of 16.7 g of Part K compound (52.5 mmol), 13.4 gof Part L compound (95% pure=12.7 g, 52.5 mmol), 7.8 g of1-hydroxybenzenetriazole monohydrate (57.8 mmol, 1.10 equiv), and 5.8 gof N-methylmorpholine (57.8 mmol, 1.10 equiv) in 250 mL of DMF (Burdick& Jackson) under argon at 0°, was added 11.1 g of WSC (57.8 mmol, 1.10equiv). The WSC dissolved completely. The mixture was allowed to warm toroom temperature overnight. No precipitate formed. The mixture wasrotoevaporated (60° bath). The residue was diluted with 700 mLEtOAc--solids did not all dissolve--and washed with 250 mL 0.3 M aqueousHCl, then 250 mL 1.0M aqueous NaHCO₃. The still undissolved solid wasdesired product according to TLC. Addition of 200 mL CH₂ Cl₂ did notgive a solution. This was washed with 150 mL 0.3M aqueous HCl plus 50 mLbrine, then 250 mL 1.0M aqueous NaHCO₃ After addition of 500 mL more CH₂Cl₂ a solution formed. This was dried over Na₂ SO₄ and evaporated invacuo. Crude title compound, 30.7 g of white solid, was obtained. Thismaterial was about 93% pure. The corrected yield (28.5 g) of titlecompound (a single diastereomer) was 100%.

    ______________________________________                                        TLC (silica gel, 10% (10% conc. aq. NH.sub.3 in CH.sub.3 OH)                  in CH.sub.2 Cl.sub.2 - anisaldehyde):                                         ______________________________________                                        Part K compound  0.42                                                         Part L compound  0.25                                                         Title compound   0.48                                                         ______________________________________                                    

    ______________________________________                                        TLC (silica gel, 50% (5% CH.sub.3 COOH in EtOAc) in                           hexane - anisaldehyde):                                                       ______________________________________                                        Part K compound  0.34                                                         Part L compound  0.00                                                         Title compound   0.12                                                         ______________________________________                                    

N.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A stirred solution of 30.7 g of crude Part M compound (93% pure=28.5 g,52.5 mmol) in 800 mL of dry CH₂ Cl₂ under argon at room temperature wascooled to 0°. As the starting material began to precipitate, 12.1 g of(C₂ H₅)₃ N (120 mmol), then 6.9 g of methanesulfonyl chloride (60 mmol)were added. The precipitate redissolved. After 40 minutes the mixturewas warmed to room temperature, and 30 minutes later it was evaporated.To the residue (crude mesylate of Part M compound) under argon, wasadded 1.0 L of acetone and 27.6 g K₂ CO₃ (200 mmol). The mixture wasrefluxed for 2 hours and refrigerated overnight. The solid was filteredoff and rinsed with acetone. TLC indicated that the solid containedproduct even after extensive rinsing. After further rinsing with CH₂Cl₂, almost all of product was extracted. The filtrate was evaporatedand flash chromatographed (500 g silica gel, 20% acetone in toluene) toobtain 24.9 g of a solid. ¹ H NMR indicated either pure title compoundas an unequal mixture of two diastereomers (90% yield) or onediastereomer of title compound plus an impurity.

    ______________________________________                                        TLC (silica gel, 20% acetone in toluene -                                     anisaldehyde):                                                                ______________________________________                                        Part M compound      0.13                                                     mesylate of Part M compound                                                                        0.21                                                     title compound       0.34                                                     ______________________________________                                    

O.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred suspension of 22.3 g (100 mmol) of cupric bromide in 250 mLof EtOAc (Burdick & Jackson) at room temperature under argon, was added30.4 g (200 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Theresulting dark mixture was stirred for 15 minutes before a solution of24.9 g of Part N compound (if pure, 47.5 mmol) in 250 mL of CHCl₃(Burdick & Jackson) was added. The mixture warmed to about 45° (simplydue to the heat of mixing of the two solvents). After 18 hours 22.3 gcupric bromide and 15.2 g DBU were added. After another 25 hours (TLCshowed almost complete reaction), 11.2 g cupric bromide and 7.6 g DBUwere added. After 4 hours more, the reaction mixture was poured into a6-L separatory funnel. A residual heavy syrup was transferred bydissolving with CH₂ Cl₂. This was shaken with 1.0 L of EtOAc and 1.4 Lof a 1:1 (vol:vol) mixture of saturated aqueous NH₄ Cl and concentratedaqueous ammonia. Separation was poor. Addition of 750 mL diethyl ether(Et₂ O) allowed good separation. Two further extractions of the aqueouslayer with 800 mL EtOAc proceeded smoothly. The extracts were dried overNa₂ SO₄ and evaporated. Flash chromatography (750 g silica gel, 25% to40% EtOAc in hexane gradient) allowed isolation of 16.5 g of pure titlecompound as a white solid. The yield of title compound was 67% assumingpure Part N compound. Also isolated was 1.8 g (6% yield) of bromo-titlecompound (brominated at the 5 position of the oxazole ring) as a gum.

    ______________________________________                                        TLC (silica gel, 20% acetone in toluene -                                     anisaldehyde):                                                                ______________________________________                                        Part N compound    0.31                                                       title compound     0.47                                                       bromo-title compound                                                                             0.61                                                       ______________________________________                                    

P.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A homogeneous solution of 16.5 g Part O ester (31.6 mmol) in 100 mL ofTHF, 500 mL of CH₃ OH, and 200 mL of 1.0M aqueous NaOH was prepared andstirred at room temperature for 5 hours. Acidification with 300 mL 1.0Maqueous HCl was followed by extraction three times with CH₂ Cl₂ (500 mL,250 mL, 250 mL). The combined extracts were dried over Na₂ SO₄ andevaporated. The crude product was recrystallized by dissolving in 1.8 Lof boiling CH₃ CN (Burdick & Jackson, minimum volume) and coolingslowly, ultimately in the freezer for 20 hours. Crystals of titlecompound (not visibly highly crystalline) were filtered, washed withrefrigerated CH₃ CN, and dried under high vacuum. This provided 14.35 gof pure title compound (89% yield), as a white solid. (The motherliquors were evaporated to 1.7 g of approximately 90% pureproduct--corrected additional yield 9%, 1.5 g). The product appeared tobe microcrystalline as judged by its powder X-ray diffraction pattern,mp 167.5°-168.5°. [α]_(D) °=+14.1° in CHCl₃ at c=2.9 g/100 mL. HPLCHI=99.64% (balance was three or more compounds, C18 column, 220 nmdetector, 43% CH₃ CN: 29% of 0.2% aqueous H₃ PO₄ :28% CH₃ OH isocraticeluent).

    ______________________________________                                        TLC (silica gel, 50% (5% CH.sub.3 COOH in EtOAc) in                           hexane - anisaldehyde):                                                       ______________________________________                                        Part O compound  0.51                                                         title compound   0.36                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 176.5, 163.9, 160.8, 141.0, 138.5, 137.8,135.9, 129.7, 129.0, 126.7, 126.5, 79.7, 78.6, 50.0, 46.9, 39.2, 37.5,37.1, 34.8, 33.3, 32.5, 29.8, 28.9, 27.4, 26.7, 26.3, 24.2.

EXAMPLE 2[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A.1-Bromo-2-[3-[[Dimethyl(1,1,2-trimethylpropyl)silyl]oxy]propyl]benzene

To a solution of 29.0 g (135 mmol) of crude Example 1 Part C alcohol and24.1 g (135 mmol, Petrarch) of thexyldimethylchlorosilane in 200 mL ofdry methylene chloride (distilled from phosphorous pentoxide) was addedat room temperature 20 mL (143 mmol, distilled from calcium hydride) oftriethylamine then 200 mg (1.64 mmol, Aldrich) of4-dimethylaminopyridine. The reaction mixture was stirred at roomtemperature for 18 hours. The resulting slurry was diluted with 100 mLof hexane, cooled to 0° with stirring for 15 minutes then filtered toremove solid triethylamine hydrochloride. The filtrate was concentratedin vacuo to give an oil. The crude oil was purified by flashchromatography (Merck silica, 15×10 cm, 1:9 ethyl acetate/petroleumether) to afford 45.5 g (127 mmol, 94%) of title compound as a colorlessliquid.

B.[1S-(1α,2α,3α,4α)]-[2-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol

To a solution of 5.00 g (14.0 mmol) of Part A compound in 30 mL of drydiethyl ether (distilled from ketyl) cooled to -100° was added dropwise15 mL (1.7M in pentane, 25 mmol, Aldrich) of t-butyllithium solutionover 15 minutes. The reaction mixture was stirred at -100° for 15minutes then at 0° for 15 minutes. The resulting pale yellow anionsolution was recooled to -78° then 30 mL of dry THF (distilled fromketyl) was introduced followed by the rapid addition of a solution of875 mg (5.61 mmol) of[3aR-(3aα,4β,7β,7aα)]-octahydro-4,7-epoxyisobenzofuran-1-ol in 10 mL ofTHF. The reaction mixture was warmed to 0°, stirred for 1 hour, quenchedwith 5 mL of water then partitioned between 100 mL of water and 25 mL ofethyl acetate. The organic layer was separated and the aqueous layer wasextracted with an additional 25 mL of ethyl acetate. The organicextracts were combined, dried (magnesium sulfate) and concentrated invacuo to give an oil. The crude oil was purified by flash chromatography(Merck silica, 12×5.0 cm, 1:4 ethyl acetate/petroleum ether then 4:1ethyl acetate/petroleum ether) to afford 2.35 g (5.41 mmol, 97%) oftitle diasteromeric alcohols as a colorless oil.

C. [1S-(1α,2α,3α,4α)-2-[[2-[3-[[Dimethyl(1,1,2-trimethylpropyl)silyl]oxy]propyl]phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-methanol

A mixture of 1.90 g (4.38 mmol) of Part B diastereomeric alcohols and1.9 g of 20% palladium hydroxide on carbon catalyst (moist, <50% water,Aldrich) in 60 mL of glacial acetic acid was stirred rapidly under anatmosphere of hydrogen (balloon) for 5 hours. The reaction mixture wasfiltered through a 4 μM polycarbonate membrane and the filtrate wasconcentrated in vacuo (room temperature bath). The residue waspartitioned between 50 mL of water and 50 mL of ethyl acetate. Theorganic layer was separated, washed with 50 mL of 1M aqueous sodiumhydroxide solution, dried (magnesium sulfate) and concentrated in vacuoto give an oil. The crude material was purified by flash chromatography(Merck silica, 12×5.0 cm, 1:2 ethyl acetate/petroleum ether) to afford1.03 g (2.39 mmol, 55%) of title compound as a colorless oil. Inaddition, 573 mg (1.37 mmol, 30%) of Part C starting material (as asingle diastereomer) was recovered.

D.[1S-(1α,2α,3α,4α)]-2-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A solution of 1.00 g (2.39 mmol) of Part C compound and 50 mg (0.41mmol, Aldrich) of 4-dimethylaminopyridine in 6 mL of 1:1 drypyridine/acetic anhydride was stirred at room temperature for 2 hours.The reaction mixture was concentrated in vacuo and the residuepartitioned between 25 mL of ethyl acetate and 20 mL 1M aqueous HClsolution. The organic layer was separated, washed with 20 mL of 1Maqueous NaOH then 20 mL of brine, dried (magnesium sulfate) andconcentrated in vacuo to afford the crude acetate as an oil.

To a solution of the crude acetate in 15 mL of reagent acetone cooled to0° was added rapidly 3.3 mL (2.6M in Cr⁺⁶, for preparation see Fieser &Fieser, "Reagents for Organic Synthesis," Vol. 1, p. 142) of Jonesreagent. The reaction mixture was stirred for 2 hours, quenched byaddition of 1 mL of isopropanol and stirred for an additional 30minutes. The resulting green slurry was filtered through a pad ofCelite. The filtrate was concentrated in vacuo and the residuepartitioned between 25 mL of diethyl ether and 25 mL of water. Theorganic layer was separated and concentrated in vacuo to give the crudeacetate-acid as an oil.

A solution of the crude acetate-acid in 15 mL of 2:1 1M aqueous NaOH/THFwas stirred at room temperature for 30 minutes. The reaction mixture wascooled in an ice-bath, quenched by addition of 15 mL of 1M aqueous HClsolution then extracted with two-25 mL portions of diethyl ether. Theether extracts were combined, washed with 25 mL of brine andconcentrated in vacuo to give the crude alcohol-acid as an oil.

A solution of the crude alcohol-acid in 10 mL of acidic methanol(prepared by addition of 0.5 mL of acetyl chloride to 10 mL of drymethanol at 0° ) was stirred at 0° for 2 hours then concentrated invacuo. The resulting oil was purified by flash chromatography (Mercksilica, 15×3.0 cm, ethyl acetate) to afford 526 mg (1.76 mmol, 74% fromPart C compound) of title compound as a colorless oil.

E.[1S-(1α,2α,3α,4α)]-2-[[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 495 mg (1.63 mmol) of Part D compound in 5 mL ofreagent acetone cooled to 0° was added rapidly 2.0 mL 2.6M in Cr⁺⁶) ofJones reagent. The reaction mixture was warmed to room temperature,stirred for 2 hours then quenched by addition of ˜1 m of isopropanol.After 15 minutes the resulting green slurry was filtered through a padof Celite. The filtrate was partitioned between 20 mL of diethyl etherand 20 mL of water. The organic layer was separated and the aqueouslayer was extracted with an additional 20 mL of diethyl ether. The etherextracts were combined, dried (magnesium sulfate) and concentrated invacuo to give 560 mg (1.59 mmol, 98%) of crude title compound as acolorless oil.

F.[1S-(1α,2α,3α,4α)]-2-[[3-[[1-(Hydroxymethyl)-2-oxo-2-(phenylmethoxy)ethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 490 mg (1.54 mmol) of Part E acid in 10 mL of dry THF(distilled from ketyl) cooled to 0° was added 392 mg (1.69 mmol, Sigma)of L-serine benzyl ester hydrochloride, 228 mg (1.69 mmol, Aldrich) of1-hydroxybenzotriazole hydrate and 530 μL (3.8 mmol, distilled fromcalcium hydride) of triethylamine. The mixture was stirred for 5 minutesthen 348 mg (1.69 mmol, Aldrich) of dicyclohexylcarbodiimide was addedin one portion. The reaction was stirred at 0° for 3 hours then warmedto room temperature for 16 hours. The resulting slurry was diluted with10 mL of ethyl acetate, cooled to 0° for 15 minutes then filtered. Thefiltrate was concentrated in vacuo to give an oil. The crude materialwas purified by flash chromatography (Merck silica, 15×3.0 cm, ethylacetate to afford 540 mg (1.09 mmol, 71%) of title compound as a whitesolid.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4,5-Dihydro-4-[(phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 525 mg (1.06 mmol) of Part F compound, 843 mg (3.10mmol, Aldrich) of triphenylphosphine and 540 μL (3.1 mmol, Aldrich) ofdiisopropylethylamine in 6 mL of 5:1 dry acetonitrile/methylene chloridewas added at room temperature 300 μL (3.1 mmol, Mallinckrodt) of reagentcarbon tetrachloride. The reaction mixture was stirred for 2 hours thendiluted with 15 mL of ethyl acetate followed by the slow addition of 15mL of saturated aqueous sodium bicarbonate solution. The resultingmixture was stirred for 5 minutes then partitioned between 20 mL ofethyl acetate and 20 mL of water. The organic layer was separated,washed with 20 mL of brine, dried (sodium sulfate) and concentrated invacuo to give a yellow oily solid. The crude material was purified byflash chromatography (Merck silica, 20×3.0 cm, 2:1 ethylacetate/petroleum ether) to afford 380 mg 0.80 mmol, 75%) of titleoxazoline as a pale yellow solid.

H.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 375 mg (0.79 mmol) of Part G oxazoline in 10 mL of drymethylene chloride (distilled from phosphorous pentoxide) was added 750mg of Example 1, Part J, nickel peroxide oxidant (K. Nakagawa et al, J.Org. Chem. 27, 1597 (62)) at room temperature. The reaction mixture wasstirred for 1 hour then an additional 190 mg of oxidant was added. After30 minutes the reaction mixture was diluted with 20 mL of ethyl acetatefollowed by the addition of 10 mL of 3M aqueous sodium bisulfitesolution. The resulting mixture was stirred rapidly for 20 minutes then10 mL of water was added. The organic layer was separated and theaqueous layer extracted with an additional 20 mL of ethyl acetate. Theorganic extracts were combined, washed with 25 mL of 1M aqueous sodiumcitrate solution, dried (magnesium sulfate) and concentrated in vacuo togive an oil. The crude material was purified by flash chromatography(Merck silica, 15×5.0 cm, 2:3 ethyl acetate/petroleum ether) to afford180.mg (0.38 mmol, 48%) of title oxazole as an oil.

I. 4-(4-Chlorophenyl)butylamine

(a) 3-(4-Chloropenyl)propanol

To a stirred solution of 5.0 g (27 mmol) of 3-(4-chlorophenyl)propionicacid in 30 ml of tetrahydrofuran at 0° C., 30 ml (1M in THF, 30 mmol) ofborane-tetrahydrofuran solution was added dropwise. The reaction wasstirred for 15 hours. The reaction mixture was concentrated in vacuo.The residue was quenched with water and partitioned between diethylether and saturated sodium bicarbonate. The organic layer was separatedand the aqueous layer was extracted twice with 40 ml of diethyl ether.The organic layers were combined and washed with brine, dried over MgSO₄and concentrated in vacuo to obtain 3.9 g of a colorless oil.

¹³ C NMR (CDCl₃, 67.8 MHz)δ: 140.0, 131.0, 129.9, 129.0, 161.0, 132.5,131.0.

(b) 3-(4-Chlorophenyl)propyl bromide

To a stirred solution of 4.15 g (15.8 mmol) of triphenylphosphine in 100ml of toluene at 0° C., 1.51 ml (15.8 mmol) of bromine was addeddropwise. This mixture was stirred for 3 hours then a solution of 3.90 g(22.9 mmol) of Part (a) alcohol and 1.63 ml (15.8 mmol) of pyridine in20 ml of toluene was added. A solution of 25 ml hexane and 25 ml diethylether was added, and a brown mass was formed. The liquid was decantedand concentrated in vacuo. The residue was triturated with hexane:ethylacetate and triphenylphosphine oxide was precipitated. The solid wasfiltered and the filtrate was concentrated in vacuo to give a yellowoil. The oil was purified by flash chromatography to obtain 1.80 g 7.72mmol, 49%) of the desired product.

¹³ C NMR (CDCl₃)δ: 138.7, 131.6, 129.6, 128.3, 33.7, 33.0, 32.5.

(c) 4-(4-Chlorophenyl)butyronitrile

To a solution of 3.10 g (13.3 mmol) of Part (b) bromide in 36 ml ofethanol stirred under argon at room temperature, was added a solution of4.26 g (65.4 mmol) of potassium cyanide in 12 ml of water. The reactionwas incomplete after 5 hours as indicated by TLC. To the reactionmixture 4 ml of THF and 4 ml of water were added, and a homogeneousreaction mixture was obtained. After stirring for 12 hours, water anddiethyl ether were added. The organic layer was separated. The aqueouslayer was extracted twice with 50 ml of diethyl ether. The organiclayers were combined, washed with water, brine, dried over MgSO₄ andconcentrated in vacuo to give an oil. The oil was purified by flashchromatography (Merck silica gel 90:10 hexane:ethyl acetate) to obtain1.80 g (10.1 mmol, 76%) of title nitrile as a clear oil.

¹³ C NMR (CDCl₃)δ: 138.0, 132.1, 129.6, 128.6, 33.5, 26.6, 16.2

(d) 4-(4-Chlorophenyl)butylamine

To a solution of 1.80 g (10 mmol) of Part (c) nitrile in 70 ml ofdiethyl ether stirred under argon at 0° C., was added 0.38 g (10 mmol)of lithium aluminum hydride. Gas was evolved. After 20 minutes, thereaction mixture was quenched with 0.4 ml of water, then 0.4 ml of 1NNaOH, then 1.2 ml water, stirring for a few minutes after each addition.The resulting white precipitate was filtered and the filtrate wasconcentrated in vacuo to obtain 1.5 g (8.20 mmol, 82%) of title amine asa clear oil.

¹³ C NMR (CDCl₃)δ: 140.7, 131.2, 129.5, 128.2, 41.8, 34.9, 33.0, 28.4

J.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A mixture of 175 mg (0.37 mmol) of Part H oxazole and 30 mg of 20%palladium hydroxide on carbon catalyst (moist, <50% water, Aldrich) in 5mL of reagent ethyl acetate was stirred under an atmosphere of hydrogen(balloon) for 1 hour. The catalyst was removed by filtration through a 4μM polycarbonate membrane. The filtrate was concentrated in vacuo toafford 141 mg (0.37 mmol, 100%) of the crude acid([1S-(1α,2α,3α,4α)]-2-[[3-[4-[carboxy]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester) as a white solid, mp 156°-158°.

To a solution of 135 mg (0.35 mmol) of the crude acid in 3 mL of drymethylene chloride (distilled from phosphorous pentoxide) was added atroom temperature a small drop of DMF then 40 μL (0.46 mmol, Aldrich) ofoxalyl chloride. The reaction mixture was stirred for 30 minutes thenconcentrated in vacuo to give the crude acid chloride as a yellow solid.The acid chloride was solubilized in 3 mL of dry methylene chloride thencooled to 0° and a solution of 84 mg (0.46 mmol) of Part I amine and 70μL (0.50 mmol, distilled from calcium hydride) of triethylamine in 1 mLof dry methylene chloride was added rapidly. The reaction mixture wasstirred for 30 minutes then partitioned between 25 mL of ethyl acetateand 15 mL of 1M aqueous HCl solution. The organic layer was separatedand the aqueous layer was extracted with an additional 10 mL of ethylacetate. The organic extracts were combined, dried (magnesium sulfate)and concentrated in vacuo to give a yellow solid. The crude material waspurified by flash chromatography (Merck silica, 18×1.5 cm, 3:1 ethylacetate/petroleum ether) to afford 161 mg (0.29 mmol, 83%) of titlecompound as a white solid, mp 140°-142°.

K.[1S-(1α,2α,3α,4α)]-2-[[3-4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A solution of 158 mg (0.29 mmol) of Part J compound and 25 mg (0.60mmol, Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/waterwas stirred rapidly at room temperature for 1.5 hours. The reaction wasacidified by addition of 2 μL of 1M aqueous HCl solution thenpartitioned between 20 mL of ethyl acetate and 20 mL of water. Theorganic layer was separated, washed with 20 mL of brine, dried(magnesium sulfate) and concentrated in vacuo to afford 152 mg (0.28mmol, 98%) of title product as a solid white foam.

IR (KBr): 3413, 2940, 1724, 1652, 1602, 1522, 1491, 1203, 1175, 1105cm⁻¹

Partial 270 MHz ¹ NMR (CDCl₃):

δ2.19 (dd, 1H),

2.32 (t, J=11, 1H),

2.55 (m, 5H),

2.89 (t, J=8, 2H),

3.39 (m, 3H),

4.39 (d, J=4, 1H),

4.96 (d, J=4, 1H),

7.12 (m, 9H),

8.14 (s, 1H)

67.5 MHz ¹³ C NMR (CDCl₃): δ27.4, 28.5, 28.8, 29.0, 29.9, 32.4, 34.7,38.8, 46.9, 50.0, 78.7, 79.7, 126.5, 126.7, 128.4, 129.0, 129.7, 131.4,135.8, 137.7, 138.4, 140.5, 141.1, 160.9, 163.9, 176.5.

MS(CI): 537, 539 (M+H)⁺

OR: [α]_(D) =+9.9° (c=1.0 in methanol)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.50, ammoniummolybdate/ceric sulfate and UV, homogeneous

Analysis Calc'd for C₃₀ H₃₃ ClN₂ O₅ :

C, 67.09; H, 6.19; N, 5.22, Cl, 6.60.,

Found: C, 67.33; H, 6.35; N, 5.13; Cl, 6.45

EXAMPLE 3[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[-[2.2.1]hept-2-yl]methyl]benzeneaceticacid

A. (3-Bromophenethyl)oxythexyldimethylsilane

To a stirred solution of 3-bromophenylacetic acid (55.8 g, 260 mmol,Aldrich) under argon at 0° C. was added 1M diborane/tetrahydrofuran(THF) solution dropwise (300 mL, 300 mmol) over one hour. This mixturewas stirred at 0° C. for 5.5 hours and then quenched slowly with water.The resulting mixture was concentrated in vacuo and the residue added to300 mL of saturated NaHCO₃ solution and extracted with diethyl ether(4×40 mL). The combined ether extracts were dried (MgSO₄), andconcentrated in vacuo to give 51.7 g of crude alcohol. To a stirredsolution of this alcohol and triethylamine (75 mL, 538 mmol) in 500 mLof dry CH₂ Cl₂ under argon at 0° C. was addedthexyldimethylsilylchloride (56.2 mL, 286 mmol) over 15 minutes. Thereaction mixture was stirred at 0° C. for 75 minutes and then at roomtemperature for 15 hours. This mixture was diluted with 500 mL ofdiethyl ether and the precipitate was filtered off. The solid was rinsedwith diethyl ether (3×300 mL). The filtrate was concentrated in vacuoand partitioned between 300 mL of saturated NH₄ Cl solution and diethylether (4×300 mL). The combined ether extracts were dried (MgSO₄) andconcentrated in vacuo. This crude product was distilled to give 76.9 g(87%) of title compound, bp 148°-154° (˜0.5 mm).

B.[1S-(1α,2α,3α,4α)]-2-[3-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]hydroxymethyl]benzene]ethoxy]dimethyl-(1,1,2-trimethylpropyl)silane

To a solution of 10.0 g (29.1 mmol) of Part A compound in 60 mL of drydiethyl ether cooled to -78° was added dropwise 30 mL (1.7m in pentane,51 mmol, Aldrich) of t-butyllithium solution over ˜15 minutes. Thereaction mixture was stirred at -78° for 15 minutes then at 0° for 30minutes. The resulting anion solution was re-cooled to -78°, 40 mL ofdry tetrahydrofuran was introduced and then a solution of 1.87 g (12.0mmol) of [3aR-(3aα,4β,7β,7aα)]-octahydro-4,7-epoxyisobenzofuran-1-ol in20 mL of tetrahydrofuran was added dropwise. After 15 minutes thereaction was warmed to 0°. After an additional 1 hour at 0°, thereaction was quenched with 5 mL of water, then added to 200 mL of waterand extracted with two-75 mL portions of ethyl acetate. The organicextracts were combined, dried (magnesium sulfate) and concentrated invacuo to give an oil. The crude oil was purified by flash chromatography(Merck silica, 23×5.0 cm, 1:4 ethyl acetate/petroleum ether then ethylacetate) to afford 4.10 g (10.1 mmol, 85%) of title compound as acolorless oil.

C.[1S-(1α,2α,3α,4α)]-2-[3-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene]ethoxy]dimethyl(1,1,2-trimethylpropyl)silane

A mixture of 4.05 g (10.0 mmol) of Part B compound and 5.50 g of 10%palladium on activated carbon (Aldrich) in 80 mL of glacial acetic acidwas shaken under an atmosphere of hydrogen (40 psi) on a Parr apparatusfor 24 hours. The resulting mixture was passed through a polycarbonatefilter to remove the catalyst and the filtrate was concentrated in vacuoto give an oil. The crude oil was partitioned between 100 mL of ethylacetate and 100 mL of water. The organic layer was separated, dried(magnesium sulfate) and concentrated in vacuo to afford 3.72 g (9.60mmol, 96%) of crude title alcohol as a colorless oil.

D.[1S-(1α,2α,3α,4α)]-3-[[3-[(Acetyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneethanol

To a solution of 4.56 g (11.3 mmol) of Part C alcohol and 1.3 mL (16mmol, Burdick and Jackson) of pyridine in 50 mL of dry methylenechloride (distilled from phosphorous pentoxide) cooled to 0° was addeddropwise a solution of 1.0 mL (14 mmol, Mallinckrodt) of acetyl chloridein 3 mL of methylene chloride. The reaction mixture was stirred for 30minutes then added to 50 mL of 1M aqueous HCl solution. The organicphase was separated, washed with 50 mL of 1M aqueous NaOH solution,dried (magnesium sulfate) and concentrated in vacuo to afford 5.05 g(11.4 mmol, quant) of crude acetate as a colorless oil. To a solution ofthe crude acetate in 30 mL of acetonitrile (Brudick and Jackson) cooledto 0° was added 1.5 mL of 48% aqueous hydrofluoric acid solution. Thereaction was stirred for 1 hour then quenched by slow addition of 20 mLof saturated aqueous sodium bicarbonate solution. The resulting mixturewas added to 100 mL of water and extracted with two-50 mL portions ofethyl acetate. The organic extracts were combined, dried (magnesiumsulfate) and concentrated in vacuo to give an oil. The crude materialwas purified by flash chromatography (Merck silica, 20×5 cm, ethylacetate) to afford 3.01 g (9.90 mmol, 88%) of title alcohol as acolorless oil.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-methanol

To a solution of 3.00 g (9.87 mmol) of Part D alcohol and 2.75 g (10.0mmol, Petrarch) of t-butylchlorodiphenylsilane in 50 mL of dry methylenechloride (distilled from phosphorous pentoxide) was added at 0° 1.7 mL(12 mmol, distilled from calcium hydride) of triethylamine then 200 mg(1.6 mmol, Aldrich) of 4-dimethylaminopyridine. The reaction mixture waswarmed to room temperature, stirred for 2 hours and the resulting slurrywashed with 50 mL of 1M aqueous hydrochloric acid then 50 mL of water,dried (magnesium sulfate) and concentrated in vacuo to give the crudesilyl ether as an oil. To a solution of the crude silyl ether in 50 mLof anhydrous diethyl ether (Mallinckrodt) cooled to -78° was added 20 mL(1.4M in diethyl ether, 28 mmol, Aldrich) of methyllithium solutiondropwise over 15 minutes. After 5 minutes the reaction was quenched with1 mL of methanol then warmed to room temperature and partitioned between50 mL of diethyl ether and 100 mL of water. The organic layer wasseparated, washed with 50 mL of brine, dried (magnesium sulfate) andconcentrated in vacuo to give an oil. The crude material was purified byflash chromatography (Merck silica, 20×5 cm, 1:1 ethyl acetate/petroleumether) to afford 4.41 g 8.82 mmol, 89%) of title alcohol as a colorlessglass.

F.[1S-(1α,2α,3α,4α)]-2-[[3-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylicacid

To a solution of 1.75 g (3.50 mmol) of Part E alcohol in 25 mL ofreagent acetone cooled to 0° was added 3.5 mL of Jones reagent (2.6M,Fieser and Fieser, "Reagents for Organic Synthesis," vol. 1, p. 142)dropwise over 5 minutes. The reaction was stirred at 0° for 1.5 hoursthen quenched by addition of ˜1 mL of isopropyl alcohol. The mixture wasstirred for 30 minutes then the resulting green slurry was filteredthrough a pad of Celite. The filtrate was partitioned between 100 mL ofwater and 75 mL of ethyl acetate. The organic layer was separated,washed with 100 mL of water, 50 mL of brine, dried (magnesium sulfate)and concentrated in vacuo to give 1.82 g (3.54 mmol, 101%) of crude acidas a solid white foam.

G.[1S-(1α,2α,3α,4α)]-2-[[[2-[[3-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo[2.2.1]-hept-3-yl]carbonyl]amino]-3-hydroxypropanoicacid, methyl ester

To a solution of 1.86 g (3.72 mmol) of Part F acid, 577 mg (3.72 mmol,Aldrich) of L-serine methyl ester hydrochloride and 502 mg (3.72 mmol,Aldrich) of 1-hydroxybenzotriazole hydrate in 20 mL of dry THF(distilled from potassium/benzophenone) cooled to 0° was added 1.1 mL(7.8 mmol, distilled from calcium hydride) of triethylamine, then after5 minutes, 766 mg (3.72 mmol, Aldrich) of 1,3-dicyclohexylcarbodiimide.The reaction mixture was allowed to warm to room temperature, stirredfor 16 hours and the resulting slurry filtered. The filtrate wasconcentrated in vacuo to give an oil. The crude material was purified byflash chromatography (Merck silica, 15×5 cm, ethyl acetate) to afford1.75 g (2.84 mmol, 76%) of title amide as a white foam.

H.[1S-(1α,2α,3α,4α)]-2-[2-[[3-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo[2.2.1]hept-3-yl]-4,5-dihydro-4-oxazolecarboxylicacid, methyl ester

To a solution of 1.65 g 2.76 mmol) of Part G amide and 2.89 g (11.0mmol, Aldrich) of triphenylphosphine in 40 mL of sieve-driedacetonitrile (Burdick and Jackson) was added 0.70 mL (7.2 mmol) ofcarbon tetrachloride then 1.1 mL (7.8 mmol, distilled from calciumhydride) of triethylamine. The solution was heated to 65° for 30 minutesthen cooled to room temperature and the resulting dark solution waspartitioned between 120 mL of saturated aqueous sodium bicarbonatesolution and 50 mL of ethyl acetate. The organic layer was separated andthe aqueous layer was extracted with an additional 50 mL of ethylacetate. The organic extracts were combined, dried (sodium sulfate) andconcentrated in vacuo to give a dark oil. The crude material waspurified by flash chromatography (Merck silica, 20×5 cm, 1:2acetone/hexane) to afford 515 mg 0.86 mmol, 31%) of title oxazoline as ayellow oil.

I.[1S-(1α,2α,3α,4α)]-2-[2-[[3-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo-[2.2.1]hept-3-yl]-4-oxazolecarboxylicacid, methyl ester

To a solution of 505 mg (0.85 mmol) of Part H oxazoline in 20 mL of drymethylene chloride (distilled from phosphorous pentoxide) was added atroom temperature in one portion 1.0 g of Example 2, Part H, nickelperoxide. The reaction mixture was stirred for 1 hour then an additional1.0 g portion of nickel peroxide was added. The reaction was againstirred for 1 hour then added was 40 mL of ethyl acetate followed by 25mL of 3M aqueous sodium bisulfite solution. The mixture was stirredrapidly for 20 minutes then to the resulting blue-green emulsion wasadded 50 mL of 1M aqueous sodium citrate solution. The mixture wasstirred for an additional 20 minutes then the organic layer wasseparated and the aqueous layer was extracted with 25 mL of ethylacetate. The organic extracts were combined, dried (magnesium sulfate)and concentrated in vacuo to give an oil. The crude oil was purified byflash chromatography (Merck silica, 15×3 cm, 1:1 ethyl acetate/petroleumether) to yield 247 mg (0.42 mmol, 49%) of title oxazole as a colorlessoil.

J.[1S-(1α,2α,3α,4α)]-N-(4-Cyclohexylbutyl)-2-[2-[[3-[2-[[(1,1-dimethylethyl)diphenylsilyl]oxy]ethyl]phenyl]methyl]-7-oxabicyclo[2.2.1]hept-3-yl]-4-oxazolecarboxamide

A solution of 240 mg (0.40 mmol) of Part I oxazole and 34 mg (0.81 mmol,Aldrich) of lithium hydroxide monohydrate in 5 mL of 4:1 THF/water wasstirred rapidly at room temperature for 1.5 hours. The reaction mixturewas acidified with 2 mL of 1M aqueous HCl solution then added to 20 mLof water and extracted with two-20 mL portions of ethyl acetate. Theorganic extracts were combined, dried (magnesium sulfate) andconcentrated in vacuo to afford the crude acid as an oil. The acid wassolubilized in toluene and concentrated in vacuo to remove residualwater. To the resulting oil was added 5 mL of sieve-dried toluene(Burdick and Jackson), a small drop of DMF then dropwise at roomtemperature 50 μL (0.52 mmol, Aldrich) of oxalyl chloride. The reactionmixture was stirred for 1 hour then concentrated in vacuo to give thecrude acid chloride as an oil. To a solution of the crude acid chloridein 5 mL of dry THF (distilled from potassium/benzophenone) cooled to 0°was added 95 mg (0.50 mmol) of cyclohexylbutylamine hydrochloride then170 μL (1.2 mmol, distilled from calcium hydride) of triethylamine. Thereaction was stirred for 1 hour then added to 20 mL of 1M aqueous HClsolution and extracted with two-20 mL portions of ethyl acetate. Theorganic extracts were combined, dried (magnesium sulfate) andconcentrated in vacuo to give an oil. The oil was purified by flashchromatography (Merck silica, 20×3 cm, 2:3 ethyl acetate/petroleumether) to afford 238 mg (0.33 mmol, 83%) of title oxazole as a colorlessoil.

K.[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.21]hept-2-yl]methyl]benzeneaceticacid

To a solution of 235 mg (0.33 mmol) of Part J oxazole in 7.5 mL of 2:1acetonitrile/methylene chloride was added at room temperature 0.35 mL of48% aqueous hydrofluoric acid. The reaction mixture was stirred for 2hours then added to 20 mL of saturated aqueous sodium bicarbonatesolution and extracted with 20 mL of ethyl acetate and 20 mL ofmethylene chloride. The organic extracts were combined, dried (magnesiumsulfate) and concentrated in vacuo to give an oil. The oil was purifiedby flash chromatography (Merck silica, 15×3 cm, ethyl acetate) to afford147 mg (0.31 mmol, 94%) of the alcohol as a white solid.

To a solution of 135 mg (0.28 mmol) of the alcohol from above in 5 mL ofreagent acetone at room temperature was added 0.35 mL (2.6M in Cr⁺⁶,Fieser & Fieser, Vol. 1, p. 142) of Jones reagent. The reaction mixturewas stirred for 45 minutes then quenched with several drops of isopropylalcohol. After 15 minutes 20 mL of ethyl acetate was added followed by20 mL of 3M aqueous sodium bisulfite solution. The mixture was stirredrapidly for 15 minutes then the organic layer was separated and theaqueous layer extracted with 20 mL of methylene chloride. The organicextracts were combined, dried (magnesium sulfate) and concentrated invacuo to a volume of ˜10 mL. The resulting solution was cooled to 0° andtreated with excess ethereal diazomethane (until a yellow colorpersisted). The excess diazomethane was quenched with glacial aceticacid and the solution concentrated in vacuo to give an oil. The oil waspurified by flash chromatography (Merck silica, 15×1.5 cm, 3:2 ethylacetate/petroleum ether) to yield 63 mg (0.12 mmol, 43%) of methyl esterof the title acid as a white foam.

A solution of 60 mg (0.12 mmol) of methyl ester and 20 mg (0.48 mmol,Aldrich) of lithium hydroxide monohydrate in 2.5 ml of 4:1 THF/water wasstirred at room temperature for 3 hours. The reaction was acidified byaddition of 1 ml of 1M aqueous HCl solution then partitioned between 20ml of ethyl acetate and 20 ml of water. The organic layer was separated,dried (magnesium sulfate) and concentrated in vacuo to give 58 mg (0.12mmol, 100% from methyl ester) of title acid as a solid white foam.

IR (KBr): 3409 (broad), 2923, 1712, 1649, 1604, 1513 cm⁻¹

Partial 270 MHz ¹ H NMR (CDCl₃):

δ2.20 (m, 1H),

2.40 (t, J=10, 1H),

2.62 (m, 1H),

3.32 (d, J=9, 1H),

3.36 (m, 2H),

3.56 (s, 2H),

4.39 (d, J=4, 1H),

4.90 (d, J=4, 1H),

6.90-7.30 (m, 4H),

8.04 (s, 1H)

67.5 MHz ¹³ C NMR (CDCl₃): δ24.2, 26.3, 26.7, 29.0, 29.7, 29.8, 33.3,35.9, 37.0, 37.5, 39.2, 41.0, 46.6, 50.6, 79.2, 79.9, 127.2, 127.3,128.6, 129.7, 133.9, 135.7, 140.0, 140.8, 161.0, 163.9, 175.0.

MS(CI): 495 (M+H)⁺

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.38, ammoniummolybdate/ceric sulfate and UV

Analysis for C₂₉ H₃₈ N₂ O₅ : C, 70.42; H, 7.74; N, 5.67;

Found: C, 70.54; H, 7.78; N, 5.57

EXAMPLE 4[1S-(1α,2α,3α,4α)]-2-[[3[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A.[1S-(1α,2α,3α,4α)]-2-[[3-(Aminocarbonyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of Example 2 Part E intermediate acid (9.13 mmol) in drybenzene (100 mL) is added, dropwise over a 10 minute period, oxalylchloride (0.96 mL, 11 mmol). After stirring for 5 hours, the reaction isconcentrated in vacuo, dissolved in dry THF (10 mL) and added dropwiseover a 5 minute period to a 0° C. solution of concentrated ammoniumhydroxide (3 mL) in THF (100 mL). The reaction is then concentrated invacuo. The residual solid is partitioned between ethyl acetate (150 mL)and 0.25 M K₂ CO₃ (25 mL). The aqueous layer is extracted with ethylacetate (25 mL). The combined organic layers are dried (Na_(a) SO₄) andconcentrated in vacuo. The residue is suspended in boiling diethyl ether(100 mL). Ethyl acetate (ca. 10 mL) is added to effect solution. Themixture is concentrated to ca. 50 mL on a steam bath, cooled to roomtemperature, seeded and chilled overnight. Title amide is obtained byfiltration.

B.[1S-(1α,2α,3α,4α)]-2-[[3-(Aminothiocarbonyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a 60° C. solution of Part A amide (0.999 mmol) in dry toluene (10 mL)is added Lawesson's Reagent (222 mg, 0.55 mmol). The reaction is stirredat 60° C. for 30 minutes, diluted with diethyl ether (50 mL), and washedwith half-saturated NaHCO₃ (2×5 mL). The organic layer is dried (Na₂SO₄) and concentrated in vacuo. The residue is passed through a shortsilica plug using 50% ethyl acetate/hexanes to yield the titlethioamide.

C.[1S-(1α,2α,3α,4α)]-2-[[3-(4-Carboxy-2-thiazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of Part B thioamide (1.41 mmol) and powdered anhydrous K₂CO₃ (390 mg, 2.82 mmol) in dry DMF (10 mL) is added, in severalportions, bromopyruvic acid (contains 0.4 mol water/mol bromoacid, 295mg, 1.69 mmol). The reaction is allowed to stir at room temperature for30 minutes. After this time, an additional 29.5 mg portion ofbromopyruvic acid is added. After an additional 1 hour, the solvent isremoved in vacuo below 30° C. The residue is suspended/dissolved inmethylene chloride (10 mL). Triethylamine (0.59 mL, 4.2 mmol) is addedfollowed by the dropwise addition of methanesulfonyl chloride (0.33 mL,4.2 mmol). After stirring for 5 minutes, the reaction is diluted withdiethyl ether (40 mL). The organic layer is extracted with 0.5M K₂ CO₃(9×10 mL). The combined aqueous layers are brought to pH 1.5 with 6N HCland extracted with diethyl ether (6×25 mL). These combined organiclayers are dried (Na₂ SO₄) and concentrated in vacuo.

D.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of Part C acid (0.120 mmol) in dry DMF (1 mL) is added1,1'-carbonyldiimidazole (20.3 mg, 0.125 mmol). The reaction is allowedto stir for 1 hour. A solution of (cyclohexylbutyl)amine hydrochloride(23.4 mg, 0.131 mmol) and triethylamine (0.020 mL, 0.14 mmol) in dry DMF(0.5 mL) is then added. The reaction is stirred for 1 hour, andconcentrated to remove DMF. The residue is taken up in diethyl ether (20mL) and 0.5N HCl (5 mL). The organic layer is dried (Na₂ SO₄) andconcentrated in vacuo. The resultant material is chromatographed(silica, ethyl acetate/hexanes) to yield title ester.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a solution of Part D amide in methanol (1 mL) is added 2N KOH (0.3mL). The reaction is stirred for 2 hours. An additional 0.3 mL portionof KOH is added. After an additional 1 hour, the reaction isconcentrated to remove methanol. The residue is dissolved in water (1mL) and 1N HCl is added to bring the pH to 2. The mixture is extractedwith methylene chloride (3×5 mL). the combined organic layers are dried(Na₂ SO₄) and concentrated in vacuo to yield title compound.

EXAMPLE 5[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid

A.[1S-(1α,2α,3α,4α)]-2-[[3-Cyano-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Vilsmeier reagent is prepared by the addition of oxalyl chloride (1mmol) to a 0° C. acetonitrile solution of DMF (1 mmol). To the reagentis added Example 4, Part A amide (1 mmol). After 45 minutes, pyridine (2mmol) is added. The reaction is then partitioned between diethyl etherand 1N HCl. The title nitrile is isolated by drying and concentratingthe organic phase.

B.[1S-(1α,2α,3α,4α)]-2-[[3-(Iminomethoxymethyl)-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester HCl salt

Gaseous HCl is bubbled into a 0° C. solution of part A nitrile (1 mmol)and methanol (2 mmol) in diethyl ether (10 mL) for 5 minutes. Themixture is allowed to stand at 0° C. for 7 days and is then concentratedto yield the title compound.

C.[1S-(1α,2α,3α,4α)]-2-[[3-[Methoxy[[2-oxo-2-[2-(trimethylsilyl)ethoxy]ethyl]imino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

Part B iminoether (1 mmol) is suspended in 10 mL of THF and stirred withglycine, 2-(trimethylsilyl)ethyl ester HCl salt (2 mmol) andtriethylamine (2 mmol). After 1 hour, the organic layer is diluted withdiethyl ether, washed with NaHCO₃ solution, dried and concentrated toyield title ester which is used for the subsequent step.

D.[1S-(1α,2α,3α,4α)]-2-[[3-[[[1-(Hydroxymethylene)-2-oxo-2-[2-(trimethylsilyl)ethoxy]ethyl]imino]methoxymethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester, monopotassium salt

To a 0° C. solution of potassium methoxide (2 mmol) is added dropwise, asolution of ethyl formate (4 mmol) and Part C ester (1 mmol). After 3hours, the potassium salt is collected by filtration and usedimmediately for the next step.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[2-(Trimethylsilyl)ethoxy]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

The Part D ester is dissolved in concentrated ammonia. After 3 hours,the solution is bubbled with N₂ to purge excess NH₃ and the residueneutralized with 1N HCl. The mixture is extracted with CH₂ Cl₂. Theorganic layers are concentrated in vacuo after drying to yield titleimidazole.

F.[1S-(1α,2α,3α,4α)]-2-[[3-(4-Carboxy-1H-imidazol-2-yl)-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of Part E imidazole (1 mmol) in THF (10 mL) is added 1.1mL of 1M tetra-n-butylammonium fluoride (in THF). After stirring for 1hour, the reaction is concentrated, diluted with water, brought to pH 7with 1N HCl, and extracted with methylene chloride. The organic layer isconcentrated after drying to yield title acid.

G.[1S-(1α,2α,3α,4α)]-2-[3-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methylester

To a stirred mixture of 1.0 mmol of Part F acid, 1.0 mmol of4-cyclohexylbutylamine hydrochloride, 1.0 mmol of 1-hydroxybenzotriazolein 10 mL of dry dimethylformamide under argon at 0° C. is addedtriethylamine (1.5 mmol). The mixture is stirred at 0° C. for 10 minutesat which time 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1 mmol) is added. The reaction mixture is stirred at 23°C. for 24 hours and concentrated in vacuo. The residue is dissolved inethyl acetate and washed with saturated NaHCO₃, dried (MgSO₄), filteredand concentrated in vacuo to provide title amide.

H.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a solution of Part G amide (1 mmol) in 10 mL of methanol is added 2mL of 2N KOH. After stirring for 4 hours, the reaction is concentratedto remove methanol. The residue is diluted with water and brought to pH2 with 1N HCl. The mixture is concentrated and the solid is extractedinto methanol. The methanol is concentrated and the residue is extractedinto 5:1 chloroform/methanol. The organics are concentrated to yieldcrude title acid which can be purified by chromatography on silica usingethyl acetate/pyridine/acetic acid/ water.

EXAMPLE 6[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]-N-(phenylsulfonyl)benzenepropanamide

To a stirred mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.0 mmol) and 4-dimethylaminopyridine (1.0 mmol) in 8 mLof dimethylformamide is added 1.0 mmol of benzenesulfonamide and 2.0mmol of triethylamine followed by 1.0 mmol of Example 1 title acid. Thismixture is stirred at room temperature for 48 hours and concentrated invacuo. The residue is partitioned between water and ethyl acetate. Theaqueous layer is acidified and extracted with ethyl acetate. Combinedethyl acetate layers are concentrated in vacuo to afford titlesulfonamide.

EXAMPLE 7[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid

A. 3-Bromobenzenemethanol

To a solution of 50.0 g (0.25 mols, Aldrich) of 3-bromobenzoic acid in100 ml of dry tetrahydrofuran (THF) cooled to 0° is added slowly 100 ml(1.0M in THF, 100 mmols, Aldrich) of borane-tetrahydrofuran complex. Thereaction is stirred at 0° for 1 hour then at room temperature for 18hours. The reaction is quenched by dropwise addition of water thenconcentrated in vacuo to remove solvent. The residue is partitionedbetween diethyl ether and 1M aqueous HCl. The organic layer isseparated, washed with 1M aqueous sodium hydroxide, brine, dried(magnesium sulfate) and concentrated in vacuo to afford title compound.

B. 3-Bromo-1-[[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]methyl]benzene

To a solution of 25.2 g (135 mmol) of crude Part A alcohol and 24.1 g(135 mmol, Petrarch) of thexyldimethylchlorosilane in 200 ml of drymethylene chloride (distilled from phosphorous pentoxide) is added atroom temperature 20 ml (143 mmol, distilled from calcium hydride) oftriethylamine then 200 mg (1.64 mmol, Aldrich) of4-dimethylaminopyridine. The reaction mixture is stirred at roomtemperature for 18 hours. The resulting slurry is diluted with 100 ml ofhexane, cooled to 0° with stirring for 15 minutes then filtered toremove solid triethylamine hydrochloride. The filtrate is concentratedin vacuo to give an oil. The crude oil is purified by flashchromatography (Merck silica) to afford title compound.

C.[1S-(1α,2α,3α,4α)]-[3-[[[Dimethylsilyl(1,1,2-trimethylpropyl)]oxy]methyl]phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol

To a solution of 4.61 g (14.0 mmol) of Part B compound in 30 ml of drydiethyl ether (distilled from ketyl) cooled to -100° is added dropwise15 ml (1.7M in pentane, 25 mmol, Aldrich) of t-butyllithium solutionover 15 minutes. The reaction mixture is stirred at -100° for 15 minutesthen at 0° for 15 minutes. The resulting anion solution is re-cooled to-78° then 30 ml of dry THF (distilled from ketyl) is introduced followedby the rapid addition of a solution of 875 mg (5.61 mmol) of[3aR-(3aα,4β,7β,7aα)]-octahydro-4,7-epoxyisobenzofuran-1-ol in 10 ml ofTHF. The reaction mixture is warmed to 0°, stirred for 1 hour, quenchedwith 5 ml of water then partitioned between 100 ml of water and 25 ml ofethyl acetate. The organic layer is separated and the aqueous layer isextracted with an additional 25 ml of ethyl acetate. The organicextracts are combined, dried (magnesium sulfate) and concentrated invacuo to give an oil. The crude oil is purified by flash chromatography(Merck silica) to afford title diastereomeric alcohols.

D.[1S-(1α,2α,3α,4α)]-[3-[[[Dimethylsilyl(1,1,2-trimethylpropyl)]oxy]methyl]phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol,diacetate

A solution of 2.20 g (5.41 mmol) of Part C diol and 50 mg (0.41 mmol,Aldrich) of 4-dimethylaminopyridine in 10 ml of 1:1 aceticanhydride/pyridine is stirred at room temperature for 6 hours. Thereaction mixture is concentrated in vacuo and the residue partitionedbetween 25 ml of ethyl acetate and 25 ml of 1M aqueous HCl. The organiclayer is separated, washed with 25 ml of 1M aqueous sodium hydroxide,dried (magnesium sulfate) and concentrated in vacuo to give titlecompound.

E.[1S-(1α,2α,3α,4α)]-3-[Hydroxy[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzoicacid, methyl ester

To a solution of 1.10 g (2.24 mmol) of Part D diacetate in 15 ml ofreagent acetone cooled to 0° is added rapidly 3.3 ml (2.6M in Cr⁺⁶, forpreparation see Fieser and Fieser, "Reagents for Organic Synthesis",vol. 1, p. 142) of Jones reagent. The reaction mixture is stirred for 2hours, quenched by addition of 1 ml of isopropanol and stirred for anadditional 30 minutes. The resulting green slurry is filtered through apad of Celite. The filtrate is concentrated in vacuo and the residuepartitioned between 25 ml of diethyl ether and 25 ml of water. Theorganic layer is separated and concentrated in vacuo to give the crudediacetate-acid as an oil.

A solution of the crude diacetate-acid in 15 ml of 2:1 1M aqueousNaOH/THF is stirred at room temperature for 90 minutes. The reactionmixture is cooled in an ice-bath, quenched by addition of 15 ml of 1Maqueous HCl solution then extracted with two-25 ml portions of diethylether. The ether extracts are combined, washed with 25 ml of brine andconcentrated in vacuo to give the crude diol-acid.

A solution of the crude diol-acid in 10 ml of diethyl ether is treatedwith ethereal diazomethane at 0° then concentrated in vacuo. Theresulting oil is purified by flash chromatography (Merck silica) toafford title compound.

F.[1S-(1α,2α,3α,4α)]-3-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

A mixture of 450 mg (1.54 mmol) of Part E diol and 450 mg of 10%palladium on carbon catalyst (Aldrich) in 10 ml of glacial acetic acidis shaken under an atmosphere of hydrogen (50 psi) for 24 hours. Thereaction is filtered and the filtrate concentrated in vacuo to give anoil. The crude material is purified by flash chromatography (Mercksilica) to give title product.

G.[1S-(1α,2α,3α,4α)]-3-[[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a solution of 450 mg (1.63 mmol) of Part F alcohol in 5 ml of reagentacetone cooled to 0° is added rapidly 2.0 ml (2.6M in Cr⁺⁶) of Jonesreagent. The reaction mixture is warmed to room temperature, stirred for2 hours then quenched by addition of ˜1 ml of isopropanol. After 15minutes the resulting green slurry is filtered through a pad of Celite.The filtrate is partitioned between 20 ml of diethyl ether and 20 ml ofwater. The organic layer is separated and the aqueous layer is extractedwith an additional 20 ml of diethyl ether. The ether extracts arecombined, dried (magnesium sulfate) and concentrated in vacuo to givethe crude title acid.

H.[1S-(1α,2α,3α,4α)]-3-[[3-[[[1-(Hydroxymethyl)-2-oxo-2-(phenylmethoxy)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a solution of 447 mg (1.54 mmol) of Part G acid in 10 ml of dry THF(distilled from ketyl) cooled to 0° is added 392 mg (1.69 mmol, Sigma)of L-serine benzyl ester hydrochloride, 228 mg (1.69 mmol, Aldrich) of1-hydroxybenzotriazole hydrate and 530 μl (3.8 mmol, distilled fromcalcium hydride) of triethylamine. The mixture is stirred for 5minutesthen 348 mg (1.69 mmol, Aldrich) of dicyclohexylcarbodiimide is added inone portion. The reaction is stirred at 0° for 3 hours then warmed toroom temperature for 16 hours. The resulting slurry is diluted with 10ml of ethyl acetate, cooled to 0° for 15 minutes then filtered. Thefiltrate is concentrated in vacuo to give an oil. The crude material ispurified by flash chromatography (Merck silica) to afford title ester.

I. [1S-(1α,2α,3α,4α)]-3-[[3-[4,5-Dihydro-4-[(phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a solution of 495 mg (1.06 mmol) of Part H ester, 843 mg (3.10 mmol,Aldrich) of triphenylphosphine and 540 μL (3.1 mmol, Aldrich) ofdiisopropylethylamine in 6 ml of 5:1 dry acetonitrile/methylene chlorideis added at room temperature 300 μL (3.1 mmol, Mallinckrodt) of reagentcarbon tetrachloride. The reaction mixture is stirred for 2 hours thendiluted with 15 ml of ethyl acetate followed by the slow addition of 15ml of saturated aqueous sodium bicarbonate solution The resultingmixture is stirred for 5 minutes then partitioned between 20 ml of ethylacetate and 20 ml of water. The organic layer is separated, washed with20 ml of brine, dried (sodium sulfate) and concentrated in vacuo. Thecrude material is purified by flash chromatography (Merck silica) toafford title oxazoline.

J.[1S-(1α,2α,3α,4α)]-3-[[3-[4-[(Phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a solution of 355 mg (0.79 mmol) of Part I oxazoline in 10 ml of drymethylene chloride (distilled from phosphorous pentoxide) is added 750mg of nickel peroxide oxidant (prepared as described in Example 2 PartH) at room temperature. The reaction mixture is stirred for 1 hour thenan additional 750 mg of oxidant is added. After 30 minutes the reactionmixture is diluted with 20 ml of ethyl acetate followed by the additionof 10 ml of 3M aqueous sodium bisulfite solution. The resulting mixtureis stirred rapidly for 20 minutes then 10 ml of water is added. Theorganic layer is separated and the aqueous layer extracted with anadditional 20 ml of ethyl acetate. The organic extracts are combined,washed with 25 ml of 1M aqueous sodium citrate solution, dried(magnesium sulfate) and concentrated in vacuo to give an oil. The crudematerial is purified by flash chromatography (Merck silica) to affordtitle oxazole.

K.[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

A mixture of 165 mg (0.37 mmol) of Part J oxazole and 30 mg of 20%palladium hydroxide on carbon catalyst (moist, <50% water, Aldrich) in 5ml of reagent ethyl acetate is stirred under an atmosphere of hydrogen(balloon) for 1 hour. The catalyst is removed by filtration through a 4μM polycarbonate membrane. The filtrate is concentrated in vacuo toafford crude acid.

To a solution of 125 mg (0.35 mmol) of the crude acid in 3 ml of drymethylene chloride (distilled from phosphorous pentoxide) is added atroom temperature a small drop of dimethylformamide (DMF) then 40 μl(0.46 mmol, Aldrich) of oxalyl chloride. The reaction mixture is stirredfor 30 minutes then concentrated in vacuo to give the crude acidchloride. The acid chloride is solubilized in 3 ml of dry methylenechloride then cooled to 0° and a solution of 84 mg (0.46 mmol) of4-chlorophenylbutylamine and 70 μl (0.50 mmol, distilled from calciumhydride) of triethylamine in 1 ml of dry methylene chloride is addedrapidly. The reaction mixture is stirred for 30 minutes then partitionedbetween 25 ml of ethyl acetate and 15 ml of 1M aqueous HCl solution. Theorganic layer is separated and the aqueous layer is extracted with anadditional 10 ml of ethyl acetate. The organic extracts are combined,dried (magnesium sulfate) and concentrated in vacuo. The crude materialis purified by flash chromatography (Merck silica) to afford titleester.

L.[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid

A solution of 151 mg (0.29 mmol) of Part K ester and 25 mg (0.60 mmol,Aldrich) of lithium hydroxide monohydrate in 6 ml of 2:1 THF/water isstirred rapidly at room temperature for 1.5 hours. The reaction isacidified by addition of 2 ml of 1M aqueous HCl solution thenpartitioned between 20 ml of ethyl acetate and 20 ml of water. Theorganic layer is separated, washed with 20 ml of brine, dried (magnesiumsulfate) and concentrated in vacuo to afford title product.

EXAMPLE 8[1S-(1α,2α,3α,4α)]-5-[[3-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]methyl]-1H-tetrazole

A.[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneacetonitrile

To a solution of 1 mmol of Example 7, Part K ester in 10 mL oftetrahydrofuran is added 2 mmol of lithium borohydride. The reactionmixture is stirred for 1 hour at 23° C. and then is quenched by theaddition of 1M HCl solution. The aqueous layer is extracted with ethylacetate. The organic layers are dried, filtered and concentrated invacuo to afford the crude alcohol. This alcohol is converted to thetitle nitrile using the procedures of Example 2 Part I(b) and I(c).

B.[1S-(1α,2α,3α,4α)]-5-[[3-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]methyl]-1H-tetrazole

A mixture of 300 mg (0.61 mmol) of Part A nitrile, 65 mg (1.0 mmol) ofsodium azide, 53 mg (1.0 mmol) of ammonium chloride and 42 mg (1.0 mmol)of lithium chloride in 5 ml of dry dimethylformamide is heated to 125°for 24 hours. The reaction is cooled and filtered. The filtrate isconcentrated in vacuo and the residue partitioned between water andethyl acetate. The aqueous layer is adjusted to pH=2 with 1M aqueousHCl. The organic layer is separated, dried (MgSO₄) and concentrated invacuo to give an oil. The crude material is purified by flashchromatography (Merck silica) to give title compound.

EXAMPLE 9[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]phenoxy]aceticacid

A. 1-Bromo-2-(methoxymethoxy)benzene

The oil was removed from 4.5 g (60% in oil, 112 mmol, Aldrich) of sodiumhydride dispersion by three-20 mL washes with hexane then the residuewas covered with 75 mL of dimethylformamide (Burdick and Jackson). Theresulting mixture was heated to about 50° and 18.1 g (105 mmol, Aldrich)of 2-bromophenol was added dropwise over 15 minutes. Vigorous gasevolution was observed. The reaction was stirred for an additional 30minutes then the resulting gray-brown solution was cooled to 0° and 9.6mL (117 mmol, Aldrich) of bromomethyl methyl ether was added dropwiseover 15 minutes. The reaction mixture was stirred for 1 hour at 0° thenat room temperature for 16 hours. The resulting slurry was partitionedbetween 200 mL of 1M aqueous sodium hydroxide solution and 150 mL of 4:1hexane/diethyl ether. The aqueous layer was separated and extracted withan additional 100 mL of 4:1 hexane/diethyl ether. The organic extractswere combined, washed with two-200 mL portions of water, dried(magnesium sulfate) and concentrated in vacuo to give 22.2 g (102 mmol,97%) of title compound as a pale yellow liquid.

B.[1S-(1α,2α,3α,4α)]-[2-(Methoxymethoxy)phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol

To a solution of 16.7 g (77.0 mmol) of Part A aryl bromide in 150 mL ofdry THF (distilled from potassium/benzophenone) cooled to -78° was addeddropwise 48 mL (1.6M in hexane, 77 mmol, Aldrich) of n-butyllithium over30 minutes. The reaction mixture was stirred at -78° for 1 hour. To theresulting white slurry of the anion was added a solution of 4.80 g (30.8mmol, of [3aR-(3aα,4β,7β,7aα)]-octahydro-4,7-epoxyisobenzofuran-1-ol in30 mL of dry THF over 5 minutes. The reaction was warmed to 0° (becomeshomogeneous), stirred for 2 hours then quenched with 5 mL of methanoland concentrated in vacuo. The residue was partitioned between 100 mL ofbrine and 100 mL of ethyl acetate then an additional 50 mL of water wasadded. The aqueous layer was separated and extracted with 100 mL ofethyl acetate. The organic extracts were combined, dried (magnesiumsulfate) and concentrated in vacuo to give an oil. The crude materialwas purified by flash chromatography (Merck silica, 22×5.0 cm, 1:2 ethylacetate/petroleum ether then ethyl acetate) to afford 8.49 g (28.9 mmol,94%) of title diol as an oil.

C. [1S-(1α,2α,3α,4α)]-2-[[2-(Methoxymethoxy)phenyl]methyl]-7-oxabicyclo-[2.2.1]heptane-3-methanol

A mixture of 8.40 g (28.6 mmol) of Part B diol and 8.0 g of 10%palladium on carbon catalyst (Aldrich) in 75 mL of glacial acetic acidwas stirred under an atmosphere of hydrogen (balloon) for 18 hours. Theresulting mixture was filtered on a Buchner funnel then passed through apolycarbonate membrane. The filtrate was concentrated in vacuo (oil pumpvacuum) to give an oil. The oil was partitioned between 75 mL of ethylacetate and 100 mL of 1M aqueous sodium hydroxide solution (pH=12 ofaqueous) then an equal volume of brine was added (100 mL). The aqueouslayer was separated and extracted with an additional 50 mL of ethylacetate. The organic extracts were combined, dried (magnesium sulfate)and concentrated in vacuo to afford 7.56 g (27.2 mmol, 95%) of titlealcohol as a colorless oil.

D.[1S-(1α,2α,3α,4α)]-2-[[2-(Methoxymethoxy)phenyl]methyl]-3-[(phenylmethoxy)methyl]-7-oxabicyclo[2.2.1]heptane

The oil was removed from 552 mg (60% in oil, 13.8 mmol, Aldrich) ofsodium hydride dispersion by three washes with petroleum ether then theresidue was covered with 15 mL of dry THF (distilled frompotassium/benzophenone). The mixture was heated to about 50° then addeddropwise was a solution of 3.50 g (12.6 mmol) of Part C alcohol in 15 mLof dry THF. Vigorous gas evolution was observed. The reaction wasstirred for an additional 30 minutes then cooled to 0°. To the resultinganion solution was added 465 mg (1.26 mmol, Fluka) oftetra-n-butylammonium iodide then dropwise 1.6 mL (14 mmol, Aldrich) ofbenzyl bromide. The reaction was stirred at 0° for 2 hours then at roomtemperature for 16 hours. The resulting mixture was quenched with 5 mLof water then partitioned between 100 mL of 1M aqueous HCl solution and50 mL of ethyl acetate. The aqueous layer was separated and extractedwith an additional 50 mL of ethyl acetate. The organic extracts werecombined, washed with 100 mL of 1M aqueous sodium hydroxide solution,dried (magnesium sulfate) and concentrated in vacuo to give 4.55 g (12.4mmol, 98%) of crude title compound as a yellow oil.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[(Phenylmethoxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]phenol

To a solution of 4.53 g (12.3 mmol) of Part D title compound in 12 mL ofdioxane (Burdick and Jackson) was added at room temperature 30 mL of 1:4concentrated HCl/methanol. The reaction was stirred for 5 hours thenconcentrated in vacuo. The residue was partitioned between 50 mL of 1Maqueous HCl solution and 75 mL of ethyl acetate then 50 mL of brine wasadded. The organic layer was separated, dried (magnesium sulfate) andconcentrated in vacuo to give an orange oil. The crude oil was purifiedby flash chromatography (Merck silica, 12×5.0 cm, 1:1:3 ethylacetate/methylene chloride/hexane) to afford 3.46 g (10.7 mmol, 87%) oftitle phenol as a pale yellow glass.

F.[1S-(1α,2α,3α,4α)]-[2-[[3-[(Phenylmethoxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

The oil was removed from 420 mg (60% in oil, 11 mmol, Aldrich) of sodiumhydride dispersion by three washes with hexane then 15 mL of dry THF(distilled from potassium/benzophenone) was added. To the resultingstirred mixture at room temperature was added dropwise a solution of3.30 g (10.2 mmol) of Part E phenol in 20 mL of dry THF over about 15minutes. Vigorous gas evolution was observed. The reaction was stirredfor an additional 30 minutes then cooled to 0° and a solution of 1.75 g(10.5 mmol, Aldrich) of ethyl bromoacetate in 2 mL of THF was addeddropwise. The reaction mixture was stirred for 1.5 hours then quenchedwith 50 mL of 1M aqueous HCl solution. The resulting mixture was addedto 50 mL of brine then extracted with 75 mL of ethyl acetate. Theorganic extract was dried (magnesium sulfate) and concentrated in vacuoto give an oil. The crude oil was purified by flash chromatography(Merck silica, 12×5.0 cm, 1:2 ethyl acetate/hexane) to afford 3.87 g(9.44 mmol, 93%) of title ester as a pale yellow oil.

G.[1S-(1α,2α,3α,4α)]-[2-[[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]methylphenoxy]aceticacid, ethyl ester

A mixture of 3.60 g (8.78 mmol) Part F ester and 180 mg of 20% palladiumhydroxide on carbon catalyst (moist, Aldrich) in 25 mL of ethyl acetatewas stirred under hydrogen (balloon) for 2 hours (TLC showed littlereaction). Added to the reaction was 12 mL of absolute ethanol then 0.3mL of concentrated HCl. The reaction was stirred for 2 hours (TLC showedlittle reaction) then an additional 360 mg of catalyst was added. Theresulting mixture was stirred for 20 hours, filtered on a Buchner funnelthen through a polycarbonate membrane. The filtrate was concentrated invacuo to give an oil. The crude oil was purified by flash chromatography(Merck silica, 15×5.0 cm, 2:1 ethyl acetate/hexane) to afford 1.20 g(3.75 mmol, 43%) of desired title alcohol as an oil and 1.48 g (4.09mmol, 47%) of corresponding acetate as an oil.

H.[1S-(1α,2α,3α,4α)]-[2-[[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

To a solution of 1.17 g (3.66 mmol) of Part G alcohol in 15 mL ofreagent acetone cooled to 0° was added rapidly 2.5 mL (2.6M in Cr⁺⁶, 6.5mmol) of Jones reagent. The reaction was stirred for 1 hour at 0° then30 minutes at room temperature. The mixture was re-cooled to 0°,quenched with 2 mL of isopropanol and stirred for an additional 30minutes. The resulting green slurry was filtered through a pad ofCelite. The filtrate was concentrated in vacuo and the residuepartitioned between 20 mL of 1M HCl solution and 20 mL of ethyl acetate.The organic extract was separated, washed with 20 mL of brine, dried(magnesium sulfate) and concentrated in vacuo to give 1.19 g (3.56 mmol,97%) of crude title acid as an oil.

I.[1S-(1α,2α,3α,4α)]-[2-[[3-[[[1-(Hydroxymethyl)-2-oxo-2-(phenylmethoxy)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

To a solution of 1.19 g (3.69 mmol) of crude Part H acid in 15 mL of dryTHF (distilled from potassium/benzophenone) cooled to 0° was added 540mg (4.00 mmol, Aldrich) of 1-hydroxybenzotriazole hydrate, 928 mg (4.00mmol, Sigma) of L-serine benzyl ester hydrochloride then 1.2 mL (8.5mmol, distilled from calcium hydride) of triethylamine. The slurry wasstirred for 5 minutes then 824 mg (4.00 mmol, Aldrich) ofdicyclohexylcarbodiimide was added. The reaction mixture was stirred at0° for 3 hours then at room temperature for 16 hours. The resultingslurry was diluted with 15 mL of ethyl acetate then filtered. Thefiltrate was concentrated in vacuo to give an oil. The crude materialwas purified by flash chromatography (Merck silica, 12×5.0 cm, ethylacetate) to afford 1.33 g (2.60 mmol, 73%) of title amide as a solid.

J. [1S-(1α,2α,3α,4α)]-[2-[[3-[4,5-Dihydro-4-[(phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

To a solution of 1.32 g (2.58 mmol) of Part I amide, 1.02 g (3.90 mmol,Aldrich) of triphenylphosphine and 0.70 mL (4.0 mmol, Aldrich) ofdiisopropylethylamine in 12 mL of 5:1 dry acetonitrile/methylenechloride was added at room temperature 380 mL (3.9 mmol) of reagentcarbon tetrachloride. The reaction was stirred for 2.5 hours then addedwas 30 mL of ethyl acetate and 30 mL of saturated sodium bicarbonatesolution. The organic layer was separated, washed with 30 mL of brine,dried (sodium sulfate) and concentrated in vacuo to give an oily solid.The crude material was purified by flash chromatography (Merck silica,15×5.0 cm, 4:1 ethyl acetate/hexane) to afford 883 mg (1.79 mmol, 69%)of title oxazoline as an oil.

K.[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[(Phenylmethoxy)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

To a solution of 860 mg (1.74 mmol) of Part J oxazoline in 15 mL of drymethylene chloride (distilled from phosphorous pentoxide) was added atroom temperature 1.7 g of nickel peroxide oxidant (prepared as describedin Example 2, Part H), in one portion. The reaction was stirred for 45minutes (incomplete by TLC) then an additional 1.7 g of oxidant wasadded. After 45 minutes an additional 0.85 g of oxidant was added. Thereaction mixture was stirred for 45 minutes (starting material consumedby TLC) then 50 mL of ethyl acetate was added followed by 100 mL of 3Maqueous sodium bisulfite solution. The mixture was stirred rapidly for30 minutes (green emulsion) then 50 mL of 1M aqueous sodium citratesolution was added. After stirring for 15 minutes two layers formed. Theorganic layer was separated and the aqueous layer was extracted with anadditional 50 mL of ethyl acetate. The combined organic extracts weredried (magnesium sulfate) and concentrated in vacuo to give an oil. Thecrude material was purified by flash chromatography (Merck silica,15×3.0 cm, 2:3 ethyl acetate/hexane) to afford 390 mg (0.79 mmol, 45%)of title oxazole as a foam.

L. [1S-(1α,2α,3α,4α)]-[2-[[3-(4-Carboxy-2-oxazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic acid,ethyl ester

A mixture of 385 mg (0.78 mmol) of Part K oxazole and 38 mg of 20%palladium hydroxide on carbon catalyst (moist, Aldrich) in 10 mL ofethyl acetate was stirred rapidly under an atmosphere of hydrogen(balloon) for 1.5 hours then magnesium sulfate was added. The reactionmixture was passed through a polycarbonate membrane. The filtrate wasconcentrated in vacuo to give 314 mg (0.78 mmol, 100%) of title oxazoleacid as a white solid, mp 151°-154°.

M.[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid, ethyl ester

To a solution of 310 mg (0.77 mmol) of Part L oxazole acid in 5 mL ofdry methylene chloride (distilled from phosphorous pentoxide) was addeda small drop of dimethylformamide then 90 μL (1.0 mmol, Aldrich) ofoxalyl chloride The reaction was stirred until gas evolution ceased,about 30 minutes, then concentrated in vacuo to give the crude acidchloride as a yellow foam. The acid chloride was solubilized in 3 mL ofdry methylene chloride then cooled to 0° and added dropwise was asolution of 192 mg (1.00 mmol) of cyclohexylbutylamine hydrochloride and280 μL (2.0 mmol, distilled from calcium hydride) of triethylamine in 5mL of dry methylene chloride. The reaction mixture was stirred for 15minutes then partitioned between 15 mL of 1M aqueous HCl solution and 25mL of ethyl acetate. The organic layer was separated, washed with 15 mLof brine, dried (magnesium sulfate) and concentrated in vacuo to give asolid. The crude material was purified by flash chromatography (Mercksilica, 10×3.0 cm, 1:1 ethyl acetate/hexane) to afford 332 mg (0.62mmol, 80%) of title oxazole amide as a white solid, mp 135°-136°.

N.[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid,

A mixture of 295 mg (0.55 mmol) of Part M ester and 46 mg (1.1 mmol,Aldrich) of lithium hydroxide monohydrate in 2.5 mL of 4:1 THF/water wasstirred at room temperature for 1.5 hours. The reaction mixture wasacidified with 2.2 mL of 1M aqueous HCl solution then partitionedbetween 20 mL of ethyl acetate and 20 mL of water. The organic layer wasseparated, dried (magnesium sulfate) and concentrated in vacuo to afford281 mg (0.55 mmol, 100%) of title product as a white solid, mp190°-191°.

IR (KBr): 3416, 2921, 1741, 1644, 1602, 1520, 1492 cm¹.

270 MHz ¹ H NMR (CDCl₃):

0.70-1.90 (m, 22H),

2.18 (dd, 1H),

2.37 (dd, J=12,12,1H),

2.70 (m, 1H),

3.40 (m, 3H),

4.53 (d, J=15, 1H),

4.67 (d, J=15, 1H),

5.04 (d, 1H),

6.76 (d, J=8, 1H),

6.93 (dd, J=7,7, 1H),

7.15 (m, 3H),

8.17 (s, 1H)

67.5 MHZ ¹³ C NMR (CDCl₃): 170.4, 164.2, 161.1, 155.4, 141.2, 135.7,131.0, 128.8, 127.7, 121.7, 111.3, 80.0, 78.9, 65.1, 49.2, 46.9, 39.3,37.5, 37.1, 33.3, 30.7, 29.9, 29.8, 28.7, 26.7, 26.4, 24.2.

MS(CI): 511 (M+H)⁺

OR: [α]_(D) =+41.8° (c=1.0 in chloroform)

TLC: R_(f) (silica gel, 1:10:90, acetic acid/methanol/methylenechloride)=0.46, ammonium molybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₉ H₃₈ N₂ O₆ : C, 68.21; H, 7.50; N, 5.49;

Found: C, 68.35; H, 7.81; N, 5.42

EXAMPLE 10[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-yl]methyl]benzenepropanoic acid

A. 7,7-Dimethyl-1-octanamine

(1) 3,3-Dimethylbutanal

To a solution of 9.4 mL (107 mmol) of oxalyl chloride in 500 mL of dryCH₂ Cl₂ at -60° was added a solution of 15.4 mL (18.5 g, 235 mmol) ofdimethyl sulfoxide in 25 mL of CH₂ Cl₂ dropwise over 10 minutes. Thereaction mixture was stirred for 10 minutes then 10 g (98 mmol, Aldrich)of 3,3-dimethyl-1-butanol was added slowly. Stirring was continued foran additional 20 minutes then 68.1 mL (489 mmol) of triethylamine wasadded, and the reaction mixture was allowed to warm to room temperature.Water (50 mL) was then added, the organic layer was separated and theaqueous layer was extracted with CH₂ Cl₂ (30 mL). The organic layerswere combined, washed sequentially with 1% aqueous HCl, water, aqueoussaturated NaHCO₃, water and brine, dried (magnesium sulfate) andconcentrated in vacuo to obtain 3.3 g (33 %) of title compound as avolatile yellow oil.

(2) (3-Carboxypropyl)-triphenylphosphonium bromide

A mixture of 100 g (599 mmol, Aldrich) of 4-bromobutyric acid and 157 g(599 mmol, Aldrich) of triphenylphosphine was heated to 130° for 2hours. The reaction was cooled to room temperature. The resulting solidwas solubilized in 250 mL of hot chloroform then diluted with 200 mL ofdiethyl ether. The mixture was cooled to room temperature then 0°. Thesolid which formed was collected by filtration and then dried undervacuum to afford 240 g (559 mmol, 93%) of title compound.

(3) 7,7-Dimethyl-4-octenoic acid

To a stirred solution of 13.7 g (31.9 mmol) of Part A(2) phosphoniumbromide in 60 mL of dry THF under argon at -15° was added dropwise 32 mL(1.72M in toluene, 57.9 mmol, Callery Chem) of potassium t-amylatesolution over 10 minutes. The mixture was stirred for 0.5 hour then tothe resulting orange reaction mixture was added slowly a solution of2.00 g (19.9 mmol) of Part A(1) aldehyde in 5 mL of THF. The reactionmixture was stirred at -15° C. for 1 hour then at room temperature for20 hours and quenched with 12 mL of glacial acetic acid. The resultingsolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate (100 mL) and saturated NaHCO₃ (100 mL). Theorganic layer was separated and the aqueous layer was extracted twicewith ethyl acetate (100 mL). The combined organic layers were washedsequentially with 1% aqueous HCl, water, saturated aqueous NaHCO₃,water, and brine, then dried (magnesium sulfate), and concentrated invacuo. The residue was purified by flash chromatography (Merck silica,gradient: 1% to 100% ethyl acetate in hexane, with 0.3% glacial aceticacid) to obtain 1.75 g (51%) of title compound.

(4) 7,7-Dimethyloctanoic acid

To a stirred solution of 1.2 g (7.0 mmol) of Part A(3) compound in 8 mLof glacial acetic acid was added 0.2 g of platinum oxide catalyst. Thismixture was stirred for 14 hours under an atmosphere of hydrogen(balloon). The reaction mixture was filtered through a Celite pad andthe filtrate was concentrated in vacuo. The residue was diluted with 50mL toluene and concentrated again. This process was repeated to obtain1.2 g (100%) of title compound as oil.

(5) 7,7-Dimethyloctanamide

To a stirred solution of 1.21 g (7.02 mmol) of Part A(4) compound in 50mL of toluene was added 3 mL (134 mmol) of oxalyl chloride. The reactionmixture was stirred for 1 hour at room temperature under argon and thenconcentrated in vacuo. The residue was diluted with 20 mL of toluene andconcentrated again. This was repeated to remove traces of oxalylchloride. The residue of the crude acid chloride was stirred in 5 mL ofmethanol and then 1.17 mL (8.43 mmol) of triethylamine and 2 mL (9M, 18mmol) of methanolic ammonia were added at room temperature under argon.After stirring for 16 hours, the reaction mixture was partitionedbetween 3 mL water and 20 mL ethyl acetate. The organic layer wasseparated and the aqueous layer was extracted twice with ethyl acetate(20 mL). The combined organic layers were washed with brine then dried(magnesium sulfate) and concentrated in vacuo to obtain a semi-solid.The semi-solid was crystallized by trituration with hexane to obtain 0.5g (42%) of title compound as a solid.

(6) 7,7-Dimethyl-1-octanamine

To a solution of 0.45 g (2.62 mmol) of Part A(5) compound in 50 mL ofdry diethyl ether stirred under argon at 0° C. was added 0.11 g (2.9mmol) of lithium aluminum hydride. Gas was evolved The reaction mixturewas stirred at room temperature for 4 days. While stirring vigorously,the reaction was cautiously quenched by sequential addition of 0.02 mLof H₂ O, 0.02 mL of 15% aqueous NaOH, 0.072 mL of H₂ O, and 1 mL ofdiethyl ether. A white precipitate formed After stirring for 0.5 hoursthe mixture was filtered and the filtrate was concentrated in vacuo toobtain 0.4 g (89%) of a yellow oil. This was crystallized by triturationwith hexane and CHCl₃ to give title amine

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a solution of 140 mg (0.36 mmol), of[1S-(1α,2α,3α,4α)]-2-[[3-[4-(carboxy)-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester prepared as described in Example 2, Part J, firstparagraph, in 4 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 smalldrop of dimethylformamide, followed by 40 μL (0.46 mmol, Aldrich) ofoxalyl chloride The reaction was stirred until gas evolution ceased(about 20 minutes), then the mixture was concentrated in vacuo to givethe crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 3 mL dry CH₂ Cl₂ (distilled fromP₂ O₅), cooled to 0° C., was added 63 mg (80% pure, equivalent to 51 mgpure amine, 0.32 mmol) of Part A amine, then a solution of 65 μL (0.46mmol, distilled from CaH₂) triethylamine in 1 mL dry CH₂ Cl₂ was addedto the reaction mixture. After 30 minutes the reaction mixture waspartitioned between 15 mL CH₂ Cl₂ and 15 mL H₂ O; the organic layer wasseparated and the aqueous layer was extracted with an additional 15 mLCH₂ Cl₂. The combined organic layers were dried (MgSO₄) and concentratedin vacuo to give a crude solid. The crude solid was flashchromatographed (Merck silica, 12×2.5 cm, 1:1 ethyl acetate:hexane) togive 135 mg (0.26 mmol, 81%) of title amine as a white solid.

C.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 134 mg (0.26 mmol) of Part B amide in 4 mL THF/1 mL H₂ Owas added 22 mg (0.51 mmol, Aldrich) of lithium hydroxide monohydrate.The reaction was stirred at room temperature for 2.5 hours, thenquenched by the addition of 1 mL 1M HCl. The mixture was partitionedbetween 20 mL H₂ O and 20 mL ethyl acetate; the organic layer wasseparated, dried (MgSO₄) and concentrated in vacuo to give a crude whitesolid. The crude solid was recrystallized (hot ethyl acetate/hexane) togive 100 mg (0.20 mmol, 77%) of title acid as a white solid, mp151°-153° C.

IR (KBr): 3409, 2950, 2932, 1726, 1649, 1603, 1520 cm⁻¹

270 MHz ¹ H NMR (CDCl₃) δ:

8.15 (s, 1H),

7.27 (s, 1H),

7.10 (m, 4H),

4.98 (d, 1H),

4.39 (d, 1H),

3.38 (m, 3H),

2.90 (t, 2H),

2.55 (t, 3H),

2.34 (t, 1H),

2.20 (dd, 1H),

1.90-1.00 (m, 14H),

0.81 (s, 9H)

67.5 MHz ¹³ C NMR (CDCl₃) δ: 176.2, 163.9, 160.8, 141.0, 138.5, 137.8,136.0, 129.7, 129.0, 126.7, 126.5, 79.7, 78.7, 50.0, 47.0, 44.2, 39.2,34.7, 32.5, 30.3, 29.9, 29.6, 29.4, 28.9, 27.4, 27.0, 24.5

MS (CI): 511 (M+H)⁺

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.20, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₀ H₄₂ N₂ O₅ :

C, 70.56; H, 8.29; N, 5.50,

Found: C, 70.44; H, 8.42; N, 5.50

Examples of additional compounds in accordance with the presentinvention which may be prepared following the procedures outlined in thespecification and working Examples include, but are not limited to thefollowing:

    __________________________________________________________________________     ##STR171##                                                                   Example                                                                            (CH.sub.2).sub.m                                                                  (CH.sub.2).sub.n                                                                     Y(posi-                                                       No.   .sub.--m                                                                          -n X  tion)                                                                             R.sup.1      R.sup.2                                                                            R                                       __________________________________________________________________________    11   1   2   O                                                                (2)                 C.sub.6 H.sub.13                                                                           CH.sub.3                                                                           CO.sub.2 H                              12   2   2   O                                                                (2)                                                                                 ##STR172##                                                                       CH.sub.3                                                                          CO.sub.2 H                                                       13   2   1   NH                                                               (3)                                                                                 ##STR173##                                                                       H   CONHSO.sub.2 CH.sub.3                                            14   1   2   S                                                                (4)                                                                                 ##STR174##                                                                       H   CH.sub.2 -5-tetrazolyl                                           15   2   3   O                                                                (2)  C.sub.6 H.sub.5                                                                   C.sub.6 H.sub.5                                                                   CO.sub.2 H                                                       16   1   2   NH                                                               (3)  CH.sub.2 C.sub.6 H.sub.5                                                          H   CH.sub.2 -5-tetrazolyl                                           17   1   2   O                                                                (2)  i-C.sub.3 H.sub.7                                                                 H   CONHSO.sub.2 C.sub.6 H.sub.5                                     18   1   3   O                                                                (2)                                                                                 ##STR175##                                                                       n-C.sub.4 H.sub.9                                                                 CONHSO.sub.2 CH.sub.2 C.sub.6 H.sub.5                            19   1   2   NH                                                               (3)                                                                                 ##STR176##                                                                       H   CO.sub.2 H                                                       20   2   2   O                                                                (3)                                                                                 ##STR177##                                                                       CH.sub.2 C.sub.6 H.sub.5                                                          CO.sub.2 CH.sub.3                                                21   1   2   S                                                                (3)  C.sub.2 H.sub.5                                                                   H   CO.sub.2 Li                                                      22   1   2   O                                                                (2)                                                                                 ##STR178##                                                                       H   CO.sub.2 C.sub.2 H.sub.5                                         23   1   2   O                                                                (2)  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                  CH.sub.3                                                                          CO.sub.2 H                                                       24   1   3   O                                                                (4)  n-C.sub.3 H.sub.7                                                                 CH.sub. 2 C.sub.6 H.sub.5                                                         CH.sub.2 -5-tetrazolyl                                           25   1   2   NH                                                               (3)  n-C.sub.5 H.sub.11                                                                H   CO.sub.2 H                                                       26   2   3   O                                                                (2)                                                                                 ##STR179##                                                                       CH.sub.3                                                                          CONHC.sub.6 H.sub.5                                              27   1   2   O                                                                (2)                                                                                 ##STR180##                                                                       CONH.sub.2                                                           28   2   0   O                                                                (3)                 n-C.sub.4 H.sub.9                                                                          n-C.sub.4 H.sub.9                                                                  CO.sub.2 H                              29   1   0   NH                                                               (2)  C.sub.6 H.sub.5                                                                   H   CONHCH.sub.3                                                     30   1   2   O                                                                (2)                                                                                 ##STR181##                                                                       H   CO.sub.2 H                                                       31   2   2   O                                                                (3)                                                                                 ##STR182##                                                                       H   CO.sub.2 H                                                       32   1   1   NH                                                               (2)                                                                                 ##STR183##                                                                       H   CONHCH.sub.2 C.sub.6 H.sub.5                                     33   1   2   O                                                                (2)                                                                                 ##STR184##                                                                       H   CO.sub.2 H                                                       __________________________________________________________________________

EXAMPLE 34[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-Piperidinylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, methyl ester

A. 1-Piperidinebutanenitrile

To a solution of 5.0 g (58.7 mMol, Aldrich) of piperidine an 8.2 mL (59mMol) of sieve-dried triethylamine, stirring at room temperature, wasadded 5.8 mL (59 mMol, Aldrich) of 4-bromobutyronitrile. After stirring1 minute, a white precipitate formed; the reaction became veryexothermic and an orange solid formed. The solid was slurried in 5 mLdichloromethane, cooled to 0° for 2 hours, then stirred at roomtemperature for 56 hours. The mixture was partitioned between 20 mLwater and 50 mL chloroform. The organic layer was separated and theaqueous layer was extracted with two 50 mL portions of chloroform. Thechloroform layers were combined, washed with saturated NaCl solution,dried (MgSO₄) and concentrated in vacuo to give a red slush. The slushwas slurried in 10 mL hexane and minimal amounts of ethyl acetate anddichloromethane until a white precipitate formed. The mixture wasfiltered to give 430 mg (2.8 mMol, 6%) of title nitrile as a whitesolid; the filtrate was concentrated in vacuo to give an additional 6.57g (43.1 mMol, 72%) of title nitrile as a reddish oil; total yield oftitle nitrile 7.0 g (45.9 mMol, 78%).

B. 1-Piperidinebutanamine

To a solution of 2.0 g (13.1 mMol) of crude Part A nitrile in 30 mLdiethyl ether, stirring at 0°, was added 550 mg (14.4 mMol) of lithiumaluminum hydride in 100 mg portions. The reaction mixture was warmed toroom temperature and stirred for 3 hours, then quenched by the slow,dropwise addition of 0.6 mL H₂ O, 0.6 mL 15% NaOH and 1.8 mL H₂ O. Afterstirring 30 minutes, the reaction mixture was filtered; the filtrate wasconcentrated in vacuo to give a yellow oil. The yellow oil wasazeotroped with toluene and with dichloromethane to give 2.0 g (12.8mMol, 100%) of title amine as a yellow oil.

C.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-Piperidinylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 300 mg (0.78 mMol) of the intermediate acid prepared inExample 2, Part J in 5 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1small drop of DMF, followed by 82 μL (0.94 mMol, Aldrich) of oxalylchloride. The reaction was stirred until gas evolution ceased (about 30minutes), then the mixture was concentrated in vacuo to give the crudeacid chloride as a pale yellow solid.

To a solution of crude acid chloride in 5 mL dry CH₂ Cl₂ (distilled fromP₂ O₅), cooled to 0°, was added 330 μL (2.34 mMol, distilled from CaH₂)triethylamine, followed by the dropwise addition of a solution of 365 mg(2.34 mMol) of Part B amine in 5 mL CH₂ Cl₂. The reaction was stirred at0° for 16 hours, then partitioned between 40 mL ethyl acetate/40 mLsaturated NaHCO₃ solution. The water layer was washed with three 20 mLportions of ethyl acetate. The combined ethyl acetate layers were dried(Na₂ SO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica, 3% (C₂ H₅)₃N/EtOAc) to give 300 mg (0.57 mmol, 74%) of title ester as a pale yellowsolid.

EXAMPLE 35[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-Piperidinylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, monolithium salt

To a mixture of 300 mg (0.57 mMol) of Example 34 ester in 6 mL distilledTHF/1.5 mL water was added 48 mg (1.15 mMol, Aldrich) of lithiumhydroxide monohydrate. The reaction was stirred vigorously for 16 hours,then concentrated in vacuo to give a crude yellow oil. The crude oil wasflash chromatographed (MCI HP-20 resin, H₂ O then 1:1 H₂ O/CH₂ CN) togive 280 mg (0.54 mMol, 95%) of title lithium salt as a whitelyophylate.

IR (KBr): 3418, 2945, 1653, 1575, 1538, 1521 cm⁻¹.

MS(CI): 510 (M+H)⁺

OR: [α]_(D) =+23.2° (c=1.0 in CHCl₃)

TLC: R_(f) (silica gel, 2:1 EtOAc/(20:6:11 pyridine/CH₃ COOH/H₂O))=0.10, ammonium molybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₉ H₃₈ N₃ O₅ Li+2.05 H₂ O:

C, 63.03; H, 7.68; N, 7.61;

Found: C, 63.13; H, 7.42; N, 7.51

EXAMPLE 36[1S-(1α,2α,3α,4α)]-2-[[3-4-[[[4-(4-Phenylmethoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A. 4-(Phenylmethoxy)benzenepropanol

The oil was removed from 2.6 g (60% in oil, 65 mmol, Aldrich) of sodiumhydride dispersion with 3 hexane washes, then 25 mL of sieve-dried DMF(Burdick & Jackson) was added. The slurry was heated to 50° (hot waterbath) and a solution of 5.00 g (30.1 mmol, Aldrich) of3-(4-hydroxyphenyl)propionic acid in 20 mL of DMF was added dropwiseover 15 minutes. The mixture was stirred until gas evolution ceased (aprecipitate formed). An additional 20 mL DMF was added and the reactionwas stirred for 1 hour. To the resulting slurry was added dropwise over5 minutes 10.3 g (60.2 mmol, Aldrich) of benzyl bromide. After stirringfor 20 hours, the slurry was partitioned between 200 mL H₂ O/200 mL 1:1EtOAc/hexane. The organic layer was separated, washed 3 times with 200mL H₂ O, dried (MgSO₄) and concentrated in vacuo to give 8.75 g of crudedibenzylated product as an oily solid.

To a solution of the crude material in 75 mL dry diethyl ether(distilled from Na/(C₆ H₅)₂ CO), stirring at 0°, was added 1.00 g (26.3mmol, Aldrich) of lithium aluminum hydride in 200 mg portions. Thereaction was stirred for 2 hours, then quenched by the slow, dropwiseaddition of H₂ O, followed by addition of 100 mL of 1M HCl.

The mixture was stirred for 15 minutes, then the organic layer wasseparated, washed with 25 mL of brine, dried (MgSO₄) and concentrated invacuo to give a crude solid. The crude solid was flash chromatographed(Merck silica, 1:1 EtOAc/hexane), then recrystallized (EtOAc/hexane) togive 4.50 g (18.6 mmol, 73%) of title alcohol as a white crystallinesolid, mp 58°-61°.

B. 4-(Phenylmethoxy)benzenebutanenitrile

To a solution of 4.00 g (16.5 mmol) of Part A alcohol, 3.2 mL (23 mmol,distilled from CaH₂) of triethylamine and 25 mL of dry CH₂ Cl₂(distilled from P₂ O₅), stirring at -20°, was added dropwise 2.27 g(19.8 mmol, Aldrich) of mesyl chloride. The reaction was stirred for 15minutes, then diluted with 50 mL of hexane. The resulting slurry waswashed 2 times with 50 mL 1M HCl, 50 mL 1:1 saturated aqueous NaHCO₃ /H₂O, then 25 mL brine, dried (MgSO₄) and concentrated in vacuo to give5.30 g (16.5 mmol, 100%) of crude mesylate as a white solid.

To a solution of 5.30 g (16.5 mmol) of crude mesylate in 25 mL DMSO(Burdick & Jackson, sieve-dried) was added 1.62 g (33.1 mmol, Aldrich)of sodium cyanide. The reaction was heated to 50° for 24 hours, cooled,added to 100 mL H₂ O and extracted with 100 mL of 4:1 hexane/ether. Theorganic layer was separated, washed 3 times with 100 mL H₂ O, dried(MgSO₄) and concentrated in vacuo to give a crude white solid. The crudesolid was recrystallized (ether/hexane) to give 2.90 g (11.6 mmol, 70%)or title nitrile as a white crystalline solid, mp 47°-48°.

C. 4-(Phenylmethoxy)benzenebutanamine, monohydrochloride

To a slurry of 500 mg (13.2 mmol, Aldrich) of lithium aluminum hydridein 40 mL dry diethyl ether (distilled from Na/C₆ H₅)₂ CO), stirring at0°, was added dropwise over 15 minutes a solution of 2.70 g (10.8 mmol)of Part B nitrile in 20 mL of dry diethyl ether. The reaction mixturewas stirred for 3 hours at room temperature, cooled to 0° and quenchedby the successive, slow addition of 0.5 mL H₂ O, 0.5 mL 15% aqueous NaOHsolution and 1.5 mL H₂ O. The mixture was warmed to room temperature andfiltered; the filtrate was concentrated in vacuo to give a crude whitesolid. To a solution of the crude solid in 25 mL CH₃ OH, stirring at 0°,was added 50 mL of cold methanolic HCl (prepared by addition of 3 mL CH₃COCl to 50 mL CH₃ OH at 0° ). To the resulting homogeneous solution wasadded 200 mL of diethyl ether; a white precipitate formed, collected ona Buchner funnel, and dried under vacuum (100°/2 hours) to give 1.90 g(6.53 mmol, 60%) of title amine hydrochloride as a white powder, mp225°-227°.

D.[1S(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Phenylmethoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol), of the intermediate acid preparedin Example 2, Part J in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) wasadded 1 small drop of DMF, followed by 310 μL (0.63 mmol, 2M/CH₂ Cl₂,Aldrich) of oxalyl chloride solution. The reaction was stirred until gasevolution ceased (about 30 minutes), then the, mixture was concentratedin vacuo to give the crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 170 μL (1.25 mmol, distilled fromCaH₂) of triethylamine, followed by the portionwise addition of 181 mg(0.62 mmol, Aldrich) of Part C amine hydrochloride. The reaction wasstirred at 0° for 2 hours, then partitioned between 100 mL ethylacetate/75 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude orange solid. Thecrude solid was flash chromatographed (Merck silica, 1:1 ethylacetate/hexane) to give 320 mg (0.53 mmol, 99%) of title ester as awhite solid.

E.[1S(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4Phenylmethoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid,

To a mixture of 250 mg (0.41 mmol) of Part D ester in 8 mL distilledTHF/2 mL water was added 34 mg (0.82 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 3 hours, thenquenched by the addition of 1.6 mL (1.60 mmol) 1M HCl solution. Themixture was partitioned between 30 mL ethyl acetate/30 mL water. Theethyl acetate layer was dried (MgSO₄) and concentrated in vacuo to give239 mg (0.39 mmol, 96%) of title acid as a crude white solid.

EXAMPLE 37[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Hydroxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a solution of 238 mg (0.39 mmol) of Example 36 acid in 10 mLsieve-dried CH₃ OH/5 mL EtOAc, stirring under argon for 15 minutes, wasadded 238 mg 10% Pd/C catalyst (Aldrich). The reaction atmosphere wasevacuated and filled 3 times with hydrogen; the reaction was stirredunder hydrogen (balloon) for 16 hours, then filtered through apolycarbonate filter. The filtrate was concentrated in vacuo to give acrude foam. The crude foam was flash chromatographed (Merck silica,0.25% CH₃ COOH/EtOAc) to give 110 mg (0.21 mmol, 54%) of title acid as awhite solid, mp decomp. at 212° (decomp.).

IR (KBr): 3402, 2929, 2849, 1717, 1652, 1646, 1603, 1515 cm⁻¹.

MS(CI): 519 (M+H)⁺.

OR: [α]_(D) =+12.7° (c=1.0 in methanol)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.31, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₀ H₃₄ N₂ O₆ :

C, 69.48; H, 6.61; N, 5.40;

Found: C, 69.84; H, 7.06; N, 5.04

EXAMPLE 38[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol), of the intermediate acid preparedin Example 2, Part J in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) wasadded 1 small drop of DMF, followed by 310 μL (0.63 mMol, 2M/CH₂ Cl₂,Aldrich) of oxalyl chloride solution. The reaction was stirred until gasevolution ceased (about 30 minutes), then the mixture was concentratedin vacuo to give the crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 50 μL (0.62 mMol, Aldrich) of propylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 100 mLethyl acetate/75 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica, 2:1 ethylacetate/hexane) to give 190 mg (0.45 mMol, 86%) of title ester as awhite solid.

EXAMPLE 39[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 190 mg (0.45 mMol) of Example 38 ester in 16 mLdistilled THF/4 mL water was added 37 mg (0.89 mMol, Aldrich) of lithiumhydroxide monohydrate. The reaction was stirred vigorously for 4 hours,then quenched by the addition of 1.8 mL (1.8 mMol) 1M HCL. The mixturewas partitioned between 80 mL ethyl acetate/60 mL water. The ethylacetate layer was separated, dried (MgSO₄) and concentrated in vacuo togive a crude white solid. The crude solid was recrystallized (hot ethylacetate/hexane) to give 155 mg (0.38 mMol, 84%) of title acid as a whitesolid, mp 165°-168°.

IR (KBr): 3409, 3403, 2961, 2876, 1726, 1707, 1646, 1603 cm⁻¹.

MS(CI): 413 (M+H)⁺.

OR: [α]_(D) =+5.4° (c=1.0 in methanol)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.20, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₃ H₂₈ N₂ O₅ :

C, 66.97; H, 6.84; N, 6.79

Found: C, 66.66; H, 6.92; N, 6.68

EXAMPLE 40[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of oxazole acid intermediateprepared in Example 2, Part J in 3 mL of dry methylene chloride(distilled from phosphorous pentoxide) was added a small drop ofdimethylformamide then 55 μL (0.63 mMol, Aldrich) of oxalyl chloride.The reaction mixture was stirred until gas evolution ceased, about 15minutes, then concentrated in vacuo to give a solid. The solid wasdissolved in 2 mL of sieve-dried benzene (Burdick and Jackson) thenconcentrated in vacuo to give the crude acid chloride as a solid. Thecrude acid chloride was dissolved in 5 mL of dry methylene chloride thencooled to 0° and added was 110 μL, (0.75 mMol, distilled from calciumhydride) of triethylamine followed by 72 μL (0.62 mMol, Aldrich) ofn-amylamine. The reaction mixture was stirred for 30 minutes thenpartitioned between 20 mL of ethyl acetate and 10 mL of 1M aqueous HClsolution. The organic layer was separated, dried (magnesium sulfate) andconcentrated in vacuo to give a solid. The crude solid was purified byflash chromatography (Merck silica, 12×3.0 cm, 2:1 ethyl acetate/hexane)to give 171 mg (0.38 mMol, 72%) of title ester as a white solid.

EXAMPLE 41[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A solution of 165 mg (0.36 mMol) of Example 40 ester and 30 mg (0.71mMol, Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/waterwas stirred rapidly at room temperature for 1.5 hours. The reactionmixture was acidified by addition of 1 mL of 1M aqueous HCl solution,added to 20 mL of water then extracted with two 15 mL portions of ethylacetate. The organic extracts were combined, dried (magnesium sulfate)and concentrated in vacuo to give 155 mg (0.35 mMol, 98%) of title acidas a white solid, mp 136°-139°.

IR(KBr): 3414 (broad), 2956, 1709, 1649, 1604, 1520 cm⁻¹.

MS(CI): 441 (M+H)⁺.

OR: [α]_(D) =+21.5° (c=0.5 in chloroform)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.50, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₅ H₃₂ N₂ O₅ :

C, 68.16; H, 7.32; N, 6.36;

Found: C, 68.18; H, 7.28; N, 6.11

EXAMPLE 42[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A. 2-Cyclohexylethylamine hydrochloride

To a solution of 50.0 g (389 mmol, Aldrich) of 2-cyclohexylethanol,127.9 g (487 mmol, Aldrich) of triphenylphosphine and 77.4 g (526 mmol,Aldrich) of phthalamide in 500 mL of dichloromethane were added dropwise100 mL (508 mmol, Aldrich) of diisopropyl azodicarboxylate. The reactionwas stirred at room temperature for 16 hours, then concentrated invacuo; the crude product was dissolved in 250 mL methanol/150 mLdichloromethane and cooled in an ice bath, followed by the dropwiseaddition of 49.5 mL (1559 mmol, Aldrich) of anhydrous hydrazine. Thereaction was monitored by tlc until complete, then azeotroped 2 timeswith toluene and concentrated in vacuo to give a solid. The crude solidwas dissolved in hot methanol, cooled to 0° and filtered to give productas a solid; the filtrate was concentrated in vacuo to give more crudeproduct. The combined crude solids were partitioned between 400 mLwater/400 mL chloroform; the chloroform layer was concentrated in vacuoto give a yellow solid. The crude solid was flash chromatographed (Mercksilica, gradient 2%-30% CH₃ OH/CH₂ Cl₂ in 5% NH₄ OH) to give 9.6 g (75.5mmol, 20%) of title amine as a yellow solid. ¹ H NMR (D₂ O) showedproduct was the amine hydrochloride.

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-Cyclohexylethyl)amino[carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of intermediate oxazole acidprepared in Example 2, Part J in 20 mL dry CH₂ Cl₂ (distilled from P₂O₅) was added 1 small drop of DMF, followed by 310 μL (0.63 mmol, 2M/CH₂Cl₂, Aldrich) of oxalyl chloride solution. The reaction was stirreduntil gas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo to give the crude acid chloride a pale yellowsolid.

To a solution of the crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledform P₂ O₅), cooled to 0°, was added 170 μL (1.25 mmol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 102 mg (0.62 mmol) of Part A amine hydrochloride in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 3 hours, then partitioned between 100 mLethyl acetate/75 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude orange solid. Thecrude solid was flash chromatographed (Merck silica, 2:1 ethylacetate/hexane) to give 100 mg (0.20 mmol, 39%) of title ester as awhite solid.

EXAMPLE 43[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 100 mg (0.20 mmol) of Part B ester in 8 mL distilledTHF/2 mL water was added 17 mg (0.40 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 3 hours, thenquenched by the addition of 810 μL (0.81 mmol) 1M HCl. The mixture waspartitioned between 40 mL ethyl acetate/30 mL water. The ethyl acetatelayer was dried (MgSO₄) and concentrated in vacuo to give a crude whitesolid. The crude solid was recrystallized (hot ethyl acetate/hexane) togive 94 mg (0.19 mmol, 97%) of title acid as a white solid, mp158°-161°.

IR (KBr): 3409, 2921, 2849, 1723, 1711, 1646, 1602 cm⁻¹.

MS(CI): 481 (M+H)⁺.

OR: [α]_(D) =+13.9° (c=1.0 in methanol).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.46, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₈ H₃₆ N₂ O₅ :

C, 69.97; H, 7.55; N, 5.83;

Found: C, 69.74; H, 7.65; N, 5.93

EXAMPLE 44[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5,5-Dimethylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A. 3,3-Dimethylbutanal

To a stirred slurry of 64.5 g (30 mmol) of pyridinium chlorochromate(PCC) and 80.5 g of Celite in 350 mL of CH₂ Cl₂ at 0° was added rapidlya solution of 20.4 g (20 mmol, Aldrich) of 3,3-dimethylbutanol in 50 mLof CH₂ Cl₂. This was stirred vigorously for 1.75 hours at which time thereaction was judged incomplete by TLC. An additional 10.4 g (48 mmol) ofPCC was added and the reaction was allowed to proceed for an additional1.75 hours. The reaction mixture was diluted with 500 mL of diethylether (ether) and then filtered through a 2 inch pad of Florisil. Thefilter cake was rinsed with 200 mL of ether. The combined filtrates wasconcentrated in vacuo at 0° C. to minimize product loss. When thefiltrate was concentrated to approximately 50 mL, it was diluted with200 mL of ether and filtered through Florisil again. The filtrate wasconcentrated in vacuo at 0° C. to afford 13.0 g (130 mmol, 65%) of titlecompound.

B. (E)-5,5-Dimethyl-2-hexenoic acid methyl ester

To a stirred solution of 6.5 g (65 mmol) of Part A compound in 55 mL ofCH₂ Cl₂ was added 24.0 g (71.8 mmol) of methyltriphenylphosphorylideneacetate. The reaction mixture was stirred for 16hours at room temperature and the concentrated in vacuo. The residue wasslowly diluted with 20 mL of ether followed by 40 mL of hexane. Thesolid was removed by filtration and the filtrate was concentrated invacuo. The residue was diluted with hexane and refrigerated. Theadditional precipitate was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was dissolved in 1:1 hexane:ether andfiltered through a short plug of silica gel. The silica gel was rinsedwith 50 mL of 1:1 hexane:ether. The combined filtrates was concentratedin vacuo to afford 7.5 g (48.1 mmol, 74%) of title compound.

C. (E)-5,5-Dimethyl-2-hexenoic acid

To a stirred solution of 7.5 g (48.1 mmol) of Part B compound in 50 mLof THF and 10 mL of CH₃ OH was added 50 mL of 2N KOH solution. This wasstirred for 72 hours and then concentrated in vacuo. The residue wasdiluted with 50 mL of water and acidified to pH=2 with 6N HCl solution.This was then extracted with two 50 mL portions of ether. The combinedether layers was washed with 20 mL of water, dried over MgSO₄ filteredand concentrated in vacuo to afford to 6.2 g (43.6 mmol, 91%) of titleunsaturated acid.

D. 5,5-Dimethylhexanoic acid

A solution of 3.0 g (21.1 mmol) of Part C acid in 50 mL of toluene wasdegassed by several vacuum-fill cycles with argon. To this solution wasthen added 0.60 g of 10% Pd/C and the atmosphere was exchanged forhydrogen. The reaction was allowed to proceed for 48 hours and then thecatalyst was removed by filtration through a short pad of Celite. Thepad was rinsed with ether and the combined filtrates were concentratedin vacuo to afford 3.00 g (20.80 mmol, 98%) of title acid.

E. 5,5-Dimethylhexaneamide

To a solution of 2.95 g (20.5 mmol) of Part D acid in 30 mL drymethylene chloride (distilled from P₂ O₅) was added one drop ofsieve-dried DMF, followed by the dropwise addition of 12.3 mL (2M/CH₂Cl₂, 24.6 mmol, Aldrich) oxalyl chloride solution. The reaction wasstirred until gas evolution ceased (approximately 30 minutes), then themixture was concentrated in vacuo and azeotroped three times withtoluene to give the crude acid chloride as a pale yellow solid.

To a solution of 7.5 mL (61.4 mmol, 8.2M) methanolic ammonia in 20 mLdry methylene chloride, stirring at 0°, was added dropwise over 30minutes a solution of crude acid chloride in 20 mL dry chloroform. Thereaction was warmed to room temperature and stirred for 18 hours, thenthe reaction mixture was partitioned between 75 mL 1M HCl and 75 mLethyl acetate. The water layer was separated and washed with 2×50 mLportions of ethyl acetate; the combined ethyl acetate layers were washedwith 100 mL 1M NaOH, 75 mL saturated NaCl solution, dried (MgSO₄) andconcentrated in vacuo to give 2.93 g (20.5 mmol, 100%) of title amide asa white solid.

F. 5,5-Dimethylhexanamine, monohydrochloride

To a slurry of 1.74 g (40.9 mmol, Aldrich) of lithium aluminum hydridein 70 mL dry ether (distilled from Na, (C₆ H₅)₂ CO), stirred at 0°, wasadded dropwise over 20 minutes a solution of 2.93 g (20.5 mmol) of PartE amide in 50 mL dry ether. The reaction was warmed to room temperatureand stirred for 32 hours, then cooled to 0° and quenched by the slowdropwise addition of 1.74 mL H₂ O, 1.74 mL 15% NaOH and 5.24 mL H₂ O.The mixture was stirred at 0° for 1 hours, then filtered; the filtratewas concentrated in vacuo to give the crude amine as a clear liquid. Thecrude amine in 20 mL sieve-dried methanol was added over 20 minutes to100 mL acidic methanol (prepared by addition of 1.6 mL of acetylchloride to 100 mL methanol) at 0°. The reaction was stirred at 0° for 1hour, concentrated in vacuo and diluted with 200 mL ether. The mixturewas cooled to 0° for 2 hours. The solid which formed was then filteredto give 880 mg (5.3 mmol, 26%) of title amine hydrochloride as a whitesolid, mp 144°-147°.

[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5,5-Dimethylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of intermediate oxazole acidprepared in Example 2, Part J in 20 mL dry methylene chloride (distilledfrom P₂ O₅) was added one drop of sieve-dried DMF, then dropwise over 10minutes was added a solution of 0.31 mL (2M/CH₂ Cl₂, 0.62 mmol, Aldrich)oxalyl chloride in 5 mL dry methylene chloride. The reaction was stirreduntil gas evolution ceased (approximately 30 minutes), then concentratedin vacuo to give the crude acid chloride as a yellow solid. To asolution of crude acid chloride in 10 mL dry methylene chloride, stirredat 0° , was added 0.17 mL (1.2 mmol) of sieve-dried triethylamine,followed by a solution of 126 mg (0.62 mmol), Part F amine hydrochloridein 7 mL dry methylene chloride over 10 minutes. The reaction was stirredat 0° for 2 hours, partitioned between 100 mL ethyl acetate and 75 mL lMHCl. The ethyl acetate layer was separated, dried (MgSO₄) andconcentrated in vacuo to give a crude orange solid. The crude solid wasrecrystallized (hot hexane) to give 199 mg (0.40 mmol, 77%) of titleester as a white solid.

EXAMPLE 45

[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5,5-Dimethylhexyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 199 mg (0.40 mmol) of Example 44 ester in 8 mL dry THF/2mL water was added 34 mg (0.80 mmol, Aldrich) lithium hydroxidemonohydrate. The mixture was stirred at room temperature for 2 hours,then quenched by the addition of 1.61 mL (1.61 mmol) lM HCl. The mixturewas partitioned between 30 mL ethyl acetate and 30 mL water; the ethylacetate layer was separated, dried (MgSO₄) and concentrated in vacuo togive a crude solid. The crude solid was recrystallized from hot ethylacetate/hexane to give 150 mg (0.31 mmol, 78%) of title acid as a whitesolid, mp 147°-149°.

IR (KBr): 3412, 2952, 1725, 1652, 1602, 1522 cm⁻¹. MS (CI): 483 (M+H)⁺.

OR: [α]_(D) =+15.8 (c=1.0 in chloroform)

TLC: R_(f) (silica gel, 1:9 methanol:methylene chloride)=0.20; ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis calc'd for C₂₈ H₃₈ N₂ O₅ : C, 69.03; H, 7.97; N, 5.75;

Found: C, 69.10; H, 7.98; N, 5.63

EXAMPLE 46 [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Methoxyphenyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A. 4-Methoxybenzenepropenoic acid,

methyl ester

To a slurry of 25.78 g (77.1 mmol, Aldrich) of methyl(triphenylphosphoranylidene)acetate in 150 mL dry THF [distilled from K,(C₆ H₅)₂ CO ] was added dropwise over 20 minutes 10.00 g (73.5 mmol,Aldrich) of p-anisaldehyde. The mixture was stirred at room temperaturefor 16 hours, then heated to reflux for 16 hours. TLC showed that thereaction had not gone to completion. A second portion of 1.22 g (3.7mmol) of methyl (triphenylphosphoranylidene)acetate was added; afterstirring 3 hours, the reaction was complete. The reaction mixture wasconcentrated in vacuo to give a white solid, which was triturated with200 mL hexane, cooled to 0° and filtered. The filtrate was concentratedin vacuo to give a crude beige solid, which was flash chromatographed(Merck silica, 4:1 hexane:ethyl acetate) to give 12.05 g (62.7 mmol,85%) of title alkene as a white solid.

B. 4-Methoxybenzenepropanoic acid, methyl ester

To a portion of 50 mL glacial acetic acid, purged with argon, was added12.05 g of 10% Pd/C (Aldrich) followed by a solution of 12.05 g (62.7mmol) of Part A alkene in 40 mL glacial CH₃ COOH. The reaction vesselwas evacuated and purged with H₂ three times, then the reaction mixturewas stirred under H₂ (1 atm) for 48 hours. The mixture was filteredthrough a polycarbonate filter; the filtrate was concentrated in vacuoand azeotroped three times with toluene to give a crude liquid. Thecrude liquid was flash chromatographed (Merck silica, 6:1 hexane/ethylacetate) to give 9.05 g (46.6 mmol, 74%) of title ester as a clearliquid.

C. 4-Methoxybenzenepropanol

To a slurry of 3.15 g (83.0 mmol, Aldrich) of lithium aluminum hydridein 100 mL dry ether (distilled from Na, (C₆ H₅)₂ CO), stirred at 0°, wasadded dropwise over 30 minutes a solution of 8.96 g (46.1 mmol) of PartB ester in 75 mL dry ether. The mixture was stirred at room temperaturefor 16 hours, cooled to 0° , then quenched by successive dropwiseaddition of 3.1 mL H₂ O, 3.1 mL 15% NaOH and 9.4 mL H₂ O. The reactionmixture was stirred at 0° for 1 hour, then filtered; the filtrate wasconcentrated in vacuo to give 6.90 g (41.5 mmol, 90% ) of crude titlealcohol as a clear liquid.

D. 4-Methoxybenzenepropanol, methane-sulfonate ester

To a solution of 6.90 g (41.5 mmol) of Part C alcohol and 8.7 mL (62.3mmol, Aldrich) of triethylamine in 150 mL dry CH₂ Cl₂ (distilled from P₂O₅), stirring at -20°, was added dropwise over 15 minutes a solution of3.9 mL (49.8 mmol, Aldrich) of methanesulfonyl chloride in 20 mL dry CH₂Cl₂. The reaction mixture was stirred at 0° for 15 minutes, then washedwith 300 mL lM HCl. The water layer was separated and extracted 2 timeswith 100 mL CH₂ Cl₂ ; Cl₂ ; the combined CH₂ Cl₂ layers were washed with200 mL saturated NaHC03, dried (MgSO₄) and concentrated in vacuo to give7.48 g (41.5 mmol, 100%) of title mesylate as a clear liquid.

E. 4-Methoxybenzenebutanenitrile

To a solution of 7.48 g (41.5 mmol) of Part D mesylate in 100 mL dryDMSO (Burdick & Jackson) was added 4.05 g (62.3 mmol, Aldrich) ofpotassium cyanide in four portions. The reaction mixture was stirred at80° for 2 hours, then added to 600 mL water/600 mL ether. The etherlayer was separated, washed 3 times with 200 mL water, then 200 mLsaturated NaCl solution, dried (MgSO₄) and concentrated in vacuo to givea crude liquid. The crude liquid was flash chromatographed (Mercksilica, 1:4 ethyl acetate/hexane) then distilled (150°, ˜/mm) to give6.26 g (35.7 mmol, 86%) of title nitrile as a pale yellow liquid.

F. 4-Methoxybenzenebutanamine

To a slurry of 1.63 g (43.0 mmol, Aldrich) of lithium aluminum hydridein 50 mL dry ether (distilled from Na (C₆ H₅)₂ CO), stirring at 0°, wasadded dropwise over 20 minutes a solution of Part E nitrile in 10 mL dryether. The reaction mixture was stirred at room temperature for 2 hours,during which it separated into two layers, then quenched by the dropwiseaddition of 1.6 mL H₂ O, 1.6 mL 15% NaOH and 4.9 mL H₂ O. The reactionmixture was stirred at 0° for 1 hour to give a white paste; the pastewas extracted 4 times with 100 mL ether. The combined ether layers wereconcentrated in vacuo to give a clear oil, which was triturated with 200mL ether to give a white precipitate. The mixture was filtered to give580 mg of product; the mother liquor was concentrated in vacuo to give2.86 g of product giving a total of 3.44 g (19.2 mmol, 80%) of titleamine as a white solid.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Methoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of acid prepared in Example 2, PartJ in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (2M/CH₂ Cl₂, 0.63 mmol, Aldrich) of oxalylchloride in 5 mL dry CH₂ Cl₂. The reaction was stirred until gasevolution ceased (about 30 minutes), then the mixture was concentratedin vacuo to give the crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mmol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 112 mg (0.62 mmol) of Part F amine in 5 mL C₂ Cl₂. The reaction wasstirred at 0° for 3 hours, then partitioned between 150 mL ethylacetate/75 mL lM HCl. The organic layer was separated, dried (MgSO₄) andconcentrated in vacuo to give a crude orange solid. The crude solid wasflash chromatographed (Merck silica, 1:1 ethyl acetate/hexane) to give230 mg (0.42 mmol, 81%) of title ester as a white solid.

EXAMPLE 47[1S-(1α,2α,3α,4α]-2-[[3-[4-[[[4-(4-Methoxyphenyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid

To a mixture of 210 mg (0.38 mmol) of Example 46 ester in 8 mL distilledTHF/2 mL water was added 32 mg (0.77 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 3 hours, thenquenched by the addition of 1.54 mL (1.54 mmol) lM HCl. The mixture waspartitioned between 40 mL ethyl acetate/30 mL water. The early acetatelayer was dried (MgSO₄) and concentrated in vacuo to give a crude whitesolid. The crude solid was recrystallized from hot ethyl acetate/hexaneto give 165 mg (0.31 mmol, 81%) of title acid as a white solid, mp125°-127° .

IR (KBr): 3406, 2936, 1724, 1644, 1603, 1512 cm⁻¹.

MS(CI): 533 (M+H)⁺

OR: [α]_(D) =+14.3° (c=1.0 in methanol) TLC: R_(f) (silica gel, 1:9methanol/methylene chloride)=0.31, ammonium molybdate/ceric sulfate andUV, homogeneous.

Analysis Calc'd for C₃₁ H₃₆ N₂ O₆ :

C, 69.90; H, 6.81; N, 5.26;

Found: C, 69.61; H, 6.71; N, 5.25

EXAMPLE 48[1S-(1α,2α,3α(E),4α)]-2-[[3-[4-[[(4-Cyclohexyl-2-butenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To stirred mixture of acid prepared as described in Example 2, Part J(520 mg, 1.35 mmol) in 50 mL of dry CH₂ Cl₂ under argon was added 2drops of DMF and 2 M solution of oxalyl chloride in CH₂ Cl₂ (0.82 mL,1.62 mmol). This mixture was stirred at 0° C. for 15 minutes and 1 hourat room temperature. The mixture was concentrated in vacuo and dilutedwith 20 mL of dry CH₂ Cl₂ . To this stirred mixture at 0° C. under argonwas added a solution of 4-cyclohexyl-2-butenylamine hydrochloride salt(307 mg, 1.62 mmol, preparation was completed by: 1. oxidation of2-cyclohexylethyl alcohol to 2-cyclohexylacetaldehyde with PCC; 2.condensation of 2-cyclohexylacetaldehyde with methyl(triphenylphosphoranylidene)acetate; 3. DIBAL-H reduction of the esterat -78° C. to give the alcohol; 4. conversion of the alcohol to aminewith diisopropylazodicarboxylate (DIAD) and phthalimide, followed by thetreatment of anhydrous hydrazine at room temperature overnight andrefluxing in CH₃ OH) and (C₂ H₅)₃ N (0.75 mL, 5.40 mmol) in 10 mL of dryCH₂ Cl₂ over 10 minutes. The mixture was stirred at 0° C. for 30 minutesand at room temperature for 1 hour. The mixture was diluted with 300 mLof EtOAc and washed with 1 N HCl solution (1×100 mL). The aqueous layerwas extracted with EtOAc (2×100 mL). The combined EtOAc extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification waseffected by flash chromatography on 45 g of Merck silica gel 60 using1:1 hexane-EtOAc as eluant to give 520 mg (74%) of title ester.

TLC: silica gel, EtOAc, R_(f) 0.90, Ce(SO₄)₂).

¹³ C of title ester (CDCl₃, 67.5 MHz): δ 173.7, 163.7, 160.2, 140.6,138.4, 137.7, 136.0, 132.4, 129.6, 128.9, 126.6, 126.4, 126.2, 79.6,78.5, 51.5, 49.9, 46.9, 40.9, 40.1, 37.7, 34.8, 33.0, 33.0, 32.3, 29.8,28.8, 27.5, 26.4, 26.2, 26.2.

EXAMPLE 49

1S-(1α,2α,3α(E),4α)]-2-[[3-[4-[[(4-Cyclohexyl-2-butenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a stirred mixture of Example 48 ester (510 mg, 0.98 mmol) in 20 mL offreshly distilled THF and 5 mL of water was added LiOH monohydrate (123mg, 2.94 mmol). The mixture was stirred at room temperature for 2 hoursat which time additional LiOH monohydrate (41 mg, 0.98 mmol) was added.The mixture was stirred at room temperature for 1.5 hours and acidifiedto pH 2 by the addition of 1 N HCl solution. The mixture was dilutedwith 0 mL of water and extracted with EtOAc (4×60 mL). The combinedEtOAc extracts were dried (MgSO₄), filtered and concentrated in vacuo.This was recrystallized in 300 mL of 3:2 hexane-EtOAc at roomtemperature to give 410 mg (81%) of pure title acid.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.50, Ce(SO₄)₂

³ C of title acid (CDCl₃ -CD₃ OD, 67.5 MHz): δ 174.3, 163.8, 160.5,140.1, 137.9, 136.7, 135.0, 131.3, 128.5, 129.1, 125.7, 125.5, 125.3,79.5, 78.4, 40.0, 39.4, 37.0, 34.0, 32.2, 32.2, 31.5, 28.5, 27.9, 26.8,25.6, 25.4, 25.4.

EXAMPLE 50[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-Cyclohexylidene-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred solution of acid prepared as described in Example 2, Part J(500 mg, 1.30 mmol) in 50 mL of dry CH₂ Cl₂ under argon at 0° was addedone drop of DMF and then added 2M solution of oxalyl chloride in CH₂ Cl₂(0.78 mL, 1.56 mmol). The mixture was stirred at 0° C. for 30 minutesand at room temperature for one hour. The mixture was concentrated invacuo and diluted with 30 mL of dry CH₂ Cl₂. To this stirred mixture wasadded a solution of 4-cyclohexylidenebutanamine (238 mg, 1.56 mmol)(preparation of the above amine completed by 1. condensation ofcyclohexanone with 4-carboxyl-butyltriphenyl phosphonium bromide. 2.conversion of acid to amide through acid chloride and ammoniumhydroxide. 3. reduction of amide to amine with lithium aluminum hydride)and (C₂ H₅)3N (0.36 mL, 2.6 mmol) in 10 mL of dry CH₂ Cl₂. This mixturewas stirred at 0° C. for one hour and poured into a mixture of 100 mL ofEtOAc and 70 mL of lN (aq) HCl solution. The aqueous layer was separatedand extracted with EtOAc (1×50 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification waseffected by flash chromatography on 50 g of Merck silica gel 60 using1:1 hexane:EtOAc as eluant to give 540 mg (80%) of title ester.

TLC: silica gel, EtOAc, R_(f) 0.90, Ce(SO₄)₂.

¹³ C NMR title ester (67.5 MHz, CDCL₃): δ 173.0, 163.7, 160.5, 140.5,138.5, 137.8, 136.1, 129.5, 128.9, 126.6, 126.4, 120.0, 79.6, 78.6,51.5, 50.0, 46.9, 38.6, 37.1, 34.8, 32.3, 29.9, 28.8, 28.6, 28.6, 27.7,27.6, 26.8, 24.4.

EXAMPLE 51

[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylidene-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a stirred solution of Example 50 ester (530 mg, 1.02 mmol) in 20 mLof freshly distilled THF and 5.0 mL of H₂ O under argon was addedLiOH.H₂ O (68 mg, 2.04 mmol). The mixture was stirred at roomtemperature for 1.5 hours at which time LiOH.H₂ O (43 mg, 1.02 mmol) wasadded. The reaction mixture was stirred at room temperature for 3 hoursand acidified at 0° C. to pH 2 by the addition of lN HCl solution. Themixture was diluted with 15 mL of H₂ O and extracted with EtOAc (4×50mL). The combined EtOAc extracts were washed once with 30 mL of brine,dried (MgSO₄), filtered and concentrated in vacuo. This wasrecrystallized in 120 mL of 3:2 hexane:EtOAc at room temperature to give399 mg (77%) of pure title acid, mp 145°-147° .

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.50, Ce(SO₄)₂.

¹³ C NMR title acid (67.5 MHz, CD₃ OD): 6 176.6, 66.4, 142.4, 141.8,140.4, 139.2, 137.5, 130.4, 27.9, 127.8, 121.7, 81.9, 80.8, 51.1, 50.3,40.2, 38.5, 36.2, 33.7, 31.1, 30.7, 30.1, 29.9, 29.2, 29.1, 28.3, 25.8.

EXAMPLE 51a[1S-(1α,2α,3α,4α)]-3-[4-[[(4-(Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-heptane-2-hexanoicacid

A solution of 130 mg of Example 1 A acid in 10 mL of ethyl acetate and1.0 mL of acetic acid was degassed via a vacuum-fill cycle with argon.To this solution was added 34 mg of 10% Pd/C and the atmosphere wasexchanged for hydrogen by two vacuum-fill cycles. A slight positivepressure was maintained through use of a hydrogen balloon. The mixturewas stirred at room temperature for 22.5 hours, diluted with CH₂ Cl₂ andfiltered through a polycarbonate filter to remove the catalyst. Thefiltrate was concentrated in vacuo. The residue was diluted with tolueneand reconcentrated. Upon addition of ethyl acetate to the residue, asmall amount of gel-like material did not dissolve. The solution wasdecanted off and concentrated in vacuo. The crude product was dissolvedin minimal hot ethyl acetate and diluted with ca. three volumes ofhexane. On cooling no solid appeared, however, after standing at 5° C.overnight a white gel-like solid formed. This was removed by filtrationand dried in vacuo. The resulting white powder was triturated in hexane,filtered and dried in vacuo to afford 61 mg of pure title acid; m.p.97(softens), 122°-3° C.

Analysis Calc'd for C₂₆ H₄₀ N₂ O₅ :

C, 67.79; H, 8.75; N, 6.08;

Found: C, 67.58; H, 8.79; N, 5.97

TLC: silica gel, 4% CH₃ OH H/CH₂ Cl₂, R_(f) =0.35, Ce(SO₄)₂.

8 a]_(D) =+23 (c=0.68, CHCl₃).

⁻⁻ C NMR (CDC13, 67.5 MHz): 6 164.2, 160.8, 140.7, 135.9, 79.5, 79.4,49.8, 47.2, 39.2, 37.5, 37.1, 33.7, 33.4, 29.9, 29.7, 29.2, 29.0, 28.1,26.7, 26.4, 24.5, 24.2.

EXAMPLE 52[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Heptylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of acid prepared in Example 2, PartJ in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (0.63 mmol, 2M/CH Cl₂, Aldrich) of oxalylchloride. The reaction was stirred until gas evolution ceased (about 30minutes), then the mixture was concentrated in vacuo to give the crudeacid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mmol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 92 μL (0.62 mmol, Aldrich) of heptylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 1.5 hours, then partitioned between 150mL ethyl acetate/75 mL lM HCl. The ethyl acetate layer was separated,dried (MgSO₄) and concentrated in vacuo to give a crude orange solid.The crude solid was flash chromatographed (Merck silica, 2:1 ethylacetate:hexane) to give 190 mg (0.39 mmol, 76%) of title ester as awhite solid.

EXAMPLE 53[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Heptylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid

To a mixture of 180 mg (0.37 mmol) of Example 52 ester in 8 mL distilledTHF/2 mL water was added 31 mg (0.75 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 3 hours, thenquenched by the addition of 1.49 mL (1.49 mmol) lM HCl. The mixture waspartitioned between 40 mL ethyl acetate/30 mL water. The ethyl acetatelayer was separated, dried (MgSO₄) and concentrated in vacuo to give acrude white solid. The crude solid was recrystallized from hot ethylacetate/hexane to give 146 mg (0.31 mmol, 84%) of title acid as a whitesolid, mp 134°-137°.

IR (KBr): 3390, 3101, 2927, 1708, 1647, 1606, 1517 cm⁻¹.

MS(CI): 469 (M+H)⁺.

OR: [α]_(D) =+16.7° (c=1.0 in methanol)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.34, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₇ H₃₆ N₂ O₅ : C, 69.20; H, 7.74; N, 5.98;

Found: C, 68.87; H, 7.72; N, 5.93

EXAMPLE 54[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzeneaceticacid, methyl ester

A. 2-[2-[[Dimethyl(1,1,2-trimethyl-propyl)silyl]oxy]ethyl]benzenebromide

2-Bromophenethyl alcohol (43.80 g, 217.9 mmol) was dissolved inanhydrous CH₂ Cl₂ (200 mL) and imidazole (16.32 g, 239.6 mmol) was addedand stirred under argon 0° C. Dimethylthexylsilyl chloride (42.83 g,239.6 mmol) was added dropwise and the reaction mixture was stirred forthree days at room temperature. It was diluted with H₂ O (50 mL) andether (100 mL) and partitioned. The aqueous layer was extracted withether (2×100 mL). The combined organic layers were washed with 5%aqueous HCl (1 time), H₂ O (1 time), aqueous NaHCO₃ (1 time), H₂ O (1time), and brine, then dried (MgSO₄) and concentrated in vacuo to obtaina yellow oil. The crude product was Kugelrohr distilled (55°-80° ) underoil pump vacuum to give the purified title compound.

[1S-(1α,2α,3α,4α)]-α-[2-[2-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]ethyl]-phenyl]-3-(hydroxymethyl)-7-oxabicyclo-[2.2.1]heptane-2-ethanol

To a solution of Part A compound (6.05 g, 17.6 mmol) under argon inanhydrous ether (25 mL) at -78° was added t-butyllithium (18.6 mL, 1.70M solution in pentane) over fifteen minutes at -78° C, then 30 minutesat 0° C. The reaction solution was cooled to -78° C. and anhydrous THF(20 mL) was added.[4aR-(4ao,58,88,8a8)]-Octahydro-5,8-epoxy-1H-2-benzopyran-3-ol (1.18 g,6.93 mmol) dissolved in anhydrous THF (10 mL) was added dropwise andstirred for fifteen minutes at -78° C. A white precipitate formed. Thereaction mixture was then warmed to 0° C. for one hour and quenched withwater (100 mL). The aqueous mixture was extracted with EtOAc (2 times)and the combined extracts were dried (MgSO₄), filtered and concentratedin vacuo to give a yellow oil. The crude product was chromatographed ona silica gel column and eluted with 30-60% EtOAc in hexane to obtaintitle compound (2.35 g, 78%) as a viscous, pale, yellow oil.

C.[1S-(1α,2α,3α,4α)]-2-[1-(Acetyloxy)-2-[3-[(acetyloxy)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

To Part B compound (2.35 g, 5.41 mmol) in pyridine (2.4 mL) under argonat 0° C. was added acetic anhydride (1.66 g, 16.2 mmol) over tenminutes. The mixture was stirred at 0° C. for one hour, then at roomtemperature for sixteen hours. The reaction mixture was diluted withether (125 mL) and washed with lN aqueous HCl (3×50 mL). The ether layerwas dried (MgSO₄), filtered and concentrated in vacuo. The residue whichcontained[1S-(1α,2α,3α,4α)]-a-[2-[2-[dimethyl(1,1,2-tri-methylpropyl)silyl]oxy]ethyl]phenyl]-3-[(acetyloxy)-methyl]-7-oxabicyclo[2.2.1]heptane-2-ethanol,acetate ester, was dissolved in acetone (40 mL) and treated with JonesReagent until the orange color persisted. The reaction mixture wasstirred for four hours at room temperature, then quenched with excessisopropyl alcohol (IPA), concentrated in vacuo and partitioned betweenwater (50 mL) and EtOAc (4×20 mL). The combined organic layers werewashed with H₂ O, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was dissolved in ether (50 mL) and treated with excess etherealdiazomethane at room temperature for one hour. A white precipitate wasremoved by filtration and the filtrate was concentrated in vacuo andchromatographed on a silica gel column and eluted with 20-30%EtOAc-hexane to give title compound (1.79 g, 82%) as a viscous,colorless oil.

D.[1S-(1α,2α,3α,4α)]-2-[2-3-[(Acetyl-oxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part C compound (1.79 g, 4.43 mmol) in methylacetate (35 mL) under argon was added 70% aqueous HClO₄ (0.83 mL) and10% Pd/C (0.18 g). The atmosphere was replaced with H₂ using an H₂filled balloon by several vacuum-fill cycles. The reaction mixture wasstirred vigorously for eight hours before the catalyst was filtered offthrough a bed of anhydrous MgSO₄. The solids were rinsed well withEtOAc. The filtrate was washed with dilute aqueous HCl. The aqueouslayer was extracted with EtOAc (3 times) and the combined organic layerswere dried (MgSO₄), filtered and concentrated in vacuo. The crude oilwas chromatographed on a silica gel column and eluted with 20-25% EtOAcin hexane to obtain title compound (1.06 g, 69%) as a viscous, colorlessoil.

E.[1S-(1α,2α,3α,4α)]-2-[2-[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part D compound

(1.05 g, 3.03 mmol) in CH₃ OH (30 mL) under argon at 0° C. was addedpotassium t-butoxide (0.37 g, 3.33 mmol). The mixture was stirred at 0°C. for fifteen minutes then at room temperature for two hours. Thereaction mixture was then concentrated and partitioned between 0.1 Naqueous HCl and ether (4×50 mL). The combined extracts were dried(MgSO₄), filtered and concentrated. The crude oil was dissolved in ethertreated with excess diazomethane (to re-esterify any hydrolyzed ester),concentrated and chromatographed on a silica gel column and eluted with50% EtOAc in hexane to obtain title compound (0.77 g, 84%) as a viscous,colorless oil.

F.[1S-(1α,2α,3α,4α)]-2-[2-[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzeneaceticacid, methyl ester

To Part E compound (0.73 g, 2.40 mmol) in acetone (20 mL) at 0° C. underargon was treated with Jones Reagent until the orange color persisted.The reaction mixture was sitrred while warming to room temperature.Forty minuts after the ice bath was removed the excess Jones Reagent wasdestroyed by the addition of IPA. After concentration the reactionmixture was partitioned between 3M aqueous NaHSO₃ and EtOAc (3 times).The combined organic layers were dried (MgSO₄), filtered andconcentrated to obtain title compound (0.75 g, 99%) as a viscouscolorless liquid.

G.[1S-(1α,2α,3α,4α)]-2-[2-[3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

Part F compound (0.37 g, 1.16 mmol), 1-hydroxybenzotriazole hydrate(0.20 g, 1.16 mmol), the hydrochloride saltofN-(4-cyclohexylbutyl)-L-serinamide (0.32 g, 1.16 mmol) and DMF werecombined under argon at 0° C. Triethylamine (0.25 g, 34.9 mmol) wasadded and stirred for five minutes.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g,1.16 mmol) was added and the reaction mixture was stirred for sixteenhours while warming to room temperature. The DMF was removed underreduced pressure and the residue was dissolved in EtOAc, washed with 1Naqueous HCl (2 times), dilute aqueous NaOH (2 times) and saturatedaqueous KHCO₃. The organic layer was dried (MgSO₄), filtered andconcentrated. The crude white solid was chromatographed on a silica gelcolumn and eluted with 2-4% CH₃ OH in CH₂ Cl₂ to obtain title compound(0.52 g, 83%) as a white solid.

H.[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[%4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part G compound (0.52 g, 0.96 mmol) andN,N-diisopropylethylamine (0.37 g, 2.87 mmol) in CH₂ Cl₂ (25 mL) at 0°C. under argon was added methanesulfonyl chloride (0.11 g, 0.96 mmol)and stirred for one hour while warming to room temperature. Additionalmethanesulfonyl chloride (0.03 g, 0.26 mmol) was added and stirring wascontinued for an additional one hour. The reaction solution wasconcentrated and the residue was diluted with acetone (25 mL). Finelypowdered K₂ CO₃ (0.40, 2.28 mmol) was added and the reaction mixture wascooled to room temperature, filtered and concentrated. The crude yellowsolid was chromatographed on a silica gel column and eluted with 50-100%EtOAc in hexane to obtain title compound (0.41 g, 82%) as a white solid.

I.[1S-(1α,2α,3α,4α)]-2-[2-[3-4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzene-aceticacid

To copper (II) bromide (0.27 g, 1.20 mmol) in EtOAc (3 mL) was added DBU(0.35 g, 2.29 mmol) and stirred for 30 minutes at room temperature. PartH compound (0.30 g, 0.57 mmol) dissolved in CHCl₃ (3 mL) was addeddropwise and stirred for 48 hours at room temperature. The reactionsolution was then poured into a 1:1 aqueous NH₄ Cl:NH₄ OH mixture andextracted with EtOAc (2 times). The combined organic extracts were dried(MgSO₄), filtered and concentrated. The crude oil was chromatographed onsilica gel column and eluted with 20-60% EtOAc in hexane to obtain titleester (0.21 g, 70%) as a white foam.

EXAMPLE 55[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzeneaceticacid

To Example 54 (0.21 g, 0.40 mmol) in H₂ O (2 mL) and THF (8 mL) wasadded lithium hydroxide monohydrate (0.051 g, 1.21 mmol) and stirredvigorously for six hours at room temperature. The reaction was coled to0° C. and acidified to pH 2.0 with 1N aqueous HCl. The acidifiedreaction mixture was extracted with EtOAc (4 times) and the combinedorganic layers were washed with brine, dried (MgSO₄), filtered andconcentrated. The crude white solid was chromatographed on a silica gelcolumn and eluted with 50-60% EtOAc in hexane with 0.25% CH₃ COOH addedto obtain title acid (0.18 g, 90%) as a white solid.

EXAMPLE 56[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

A. 3-[2-[[Dimethyl(1,1,2-trimethyl-propyl)silyl]oxy]ethyl]benzenebromide

3-Bromophenethyl alcohol (46.0 g, 228.78 mmol) was combined withdimethylaminopyridine (6.99 g, 57.19 mmol) and triethylamine (34.73 g,343.17 mmol) in anhydrous CH₂ Cl₂ (200 mL) and cooled to 0° C.Dimethylhexylsilyl chloride (44.18 g, 247.08 mmol) was added dropwiseover ten minutes, then the reaction mixture was warmed to roomtemperature and stirred for sixteen hours. The reaction mixture wasdiluted with hexane (800 mL) and filtered. The filtrate was concentratedand the residue was partitioned between ether (800 mL) and 0.3N aqueousHCl (2 times with 400 mL), saturated aqueous NaHCO₃ (400 mL), dried(MgSO₄) and concentrated. The crude liquid was chromatographed on asilica gel column and eluted with 20% ether in hexane to give titlecompound (74.45 g, 95%) as a clear liquid.

30 B.[1S-(1α,2α,3α,4α)]-α-[3-[2-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]ethyl]-phenyl]-3-(hydroxymethyl)-7-oxabicyclo-[2.2.1]heptane-2-ethanol

To a solution of Part A compound (4.84 g, 4.1 mmol) under argon inanhydrous ether (30 mL) at -78° was added t-butyllithium (14.9 mL, 1.70M solution in pentane) over fifteen minutes at -78° C, then 30 minutesat 0° C. The reaction solution was cooled to -78° C. and anhydrous THF(20 mL) was added. (endo)-Octahydro-5,8-epoxy-1H-benzopyran-3-ol (1.0 g,5.88 mmol) dissolved in anhydrous THF (10 mL) was added dropwise and.stirred for fifteen minutes at -78° C. A white precipitate formed. Thereaction mixture was then warmed to 0° C. for one hour and quenched withwater (100 mL). The aqueous mixture was extracted with EtOAc (2 times)and the combined extracts were dried (MgSO₄), filtered and concentratedto give a yellow oil. The crude product was chromatographed on a silicagel column and eluted with 50-80% EtOAc in hexane to obtain titlecompound (2.11 g 82%) as a viscous, pale, yellow oil.

C.[1S-(1α,2α,3α,4α)]-3-[1-(Acetyloxy)-2-[3-[(acetyloxy)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

To Part B compound (3.65 g, 8.40 mmol) in pyridine (4.07 mL) under argonat 0° C. was added acetic anhydride (2.57 g, 25.2 mmol) over tenminutes. The mixture was stirred at 0° C. for one hour, then at roomtemperature for sixteen hours. The reaction mixture was diluted withether (200 ml) and washed with lN aqueous HCl (3 times with 50 mL). Theether layer was dried (MgSO ), filtered and concentrated. The residuewas dissolved in acetone (60 mL) and treated with Jones Reagent untilthe orange color persisted. The reaction mixture was stirred for fourhours at room temperature, then quenched with excess IPA, concentratedand partitioned between water (70 mL) and EtOAc (4 times with 50 mL).The combined organic layers were washed with H₂ O, dried (MgSO₄),filtered and concentrated. The residue was dissolved in ether (70 mL)and treated with excess ethereal diazomethane at room temperature forone hour. A white precipitate was removed by filtration and the filtratewas concentrated and chromatographed on a silica gel column and elutedwith 20-30% EtOAc-hexane to give title compound (2.99 g, 88%) as aviscous, colorless oil.

D.[1S-(1α,2α,3α,4α)]-3-[2-[3-[(Acetyl-oxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part C compound (2.99 g, 7.39 mmol) in methylacetate (55 mL) under argon was added 70% aqueous HClO₄ (1.40 mL) and10% Pd/C (0.30 g). The atmosphere was replaced with H₂ using an H₂filled balloon by several vacuum-fill cycles. The reaction mixture wasstirred vigorously for four hours before the catalyst was filtered offthrough a bed of anhydrous MgSO₄. The solids were rinsed well withEtOAc. The filtrate was washed with aqueous KHCO₃ The aqueous layer wasextracted with EtOAc (2 times) and the combined organic layers weredried (MgSO₄), filtered and concentrated. The crude oil waschromatographed on a silica gel column and eluted with 10-20% EtOAc inhexane to obtain title compound (1.83 g, 72%) as a viscous, colorlessoil..

E.[1S-(1α,2α,3α,4α)]-3-[2-[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part D compound (1.83 g, 5.31 mmol) in CH₃ OH(50 mL) under argon at 0° C. was added potassium t-butoxide (0.66 %,5.84 mmol). The mixture was stirred at 0° C. for fifteen minutes then atroom temperature for two hours. The reaction mixture was thenconcentrated and partitioned between 0.1N aqueous HCl and ether (4 timeswith 50 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated. The crude oil was dissolved in ether treated with excessdiazomethane (to re-esterify any hydrolyzed ester), concentrated andchromatographed on a silica gel column and eluted with 50% EtOAc inhexane to obtain title compound (1.16 g, 72%) as a viscous, colorlessoil.

F.[1S-(1α,2α,3α,4α)]-3-[2-3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzeneaceticacid, methyl ester

Part E compound (0.51 g, 1.68 mmol) in acetate (20 mL) at 0° C. underargon was treated with Jones Reagent until the orange color persisted.The reaction mixture was stirred while warming to room temperature.Forty minutes after the ice bath was removed the excess Jones Reagentwas destroyed by the addition of IPA. After concentration, the reactionmixture was partitioned between 3M aqueous NaHSO₃ and EtOAc (3 times).The combined organic layers were dried (MgSO₄), filtered andconcentrated to obtain title compound (0.54 g, 100%) as a viscous,colorless liquid.

G.[1S-(1α,2α,3α,4α)]-3-[2-[3-[[[2-(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, methyl ester

Part F compound (0.30 g, 0.94 mmol), 1-hydroxybenzotriazole hydrate(0.13 g, 0.94 mmol) the hydrochloride salt ofN-(4-cyclohexylbutyl)-L-serinamide (0.26 g, 0.94 mmol) and DMF werecombined under argon at 0° C. Triethylamine (0.29 g, 2.83 mmol) wasadded and stirred for five minutes.1-(3-Dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride (0.18 g,0.94 mmol) was added and the reaction mixture was stirred for sixteenhours while warming to room temperature. The DMF was removed underreduced pressure and the residue was dissolved in EtOAc, washed with 1Naqueous HCl (2 times), dilute aqueous NaOH (2 times) and saturatedaqueous KHCO . The organic layer was dried (MgSO₄), filtered andconcentrated. The crude white solid was chromatographed on a silica gelcolumn and eluted with 2-4% CH₃ OH in CH₂ Cl₂ to obtain title compound(0.46 g, 86%) as a white solid.

H.1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzeneaceticacid, methyl ester

To a stirred solution of Part G compound (0.44 g, 0.81 mmol) andN,N-diisopropylethylamine (0.31 g, 2.43 mmol) in CH₂ Cl₂ (25 mL) at 0°C. under argon was added methanesulfonyl chloride (0.093 g, 0.81 mmol)and stirred for one hour while warming to room temperature. The reactionsolution was concentrated and the residue was diluted with acetone (25mL). Finely powdered K₂ CO₃ (0 34 g, 2.43 mmol) was added and thereaction mixture was cooled at room temperature, filtered andconcentrated. The crude yellow solid was chromatographed on silica gelcolumn and eluted with 50-100% EtOAc in hexane to obtain title compound(0.41 g, 95%) as a white solid.

I.[1S-(1α,2α,3α,4α)]-3-2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzene-aceticacid, methyl ester

To copper (II) bromide (0.34 g, 1.52 mmol) in EtOAc (3 mL) was added DBU(0.44 g, 2.90 mmol) and stirred for 30 minutes at room temperature. PartH compound (0.38 g, 0.72 mmol) dissolved in CHCl₃ (3 mL) was addeddropwise and stirred for 48 hours at room temperature. The reactionsolution was then poured into a 1:1 aqueous NH₄ Cl:NH₄ OH mixture andextracted with EtOAc (2 times). The combined organic extracts were dried(MgSO₄), filtered and concentrated. The crude oil was chromatographed ona silica gel column and eluted

with 20-50% EtOAc in hexane to obtain title ester (0.21 g, 55%) as awhite foam.

EXAMPLE 57[1S-(1α,2α,3α,4α)]-3-[2-3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept--yl]ethyl]benzeneaceticacid

To Example 56 ester (0.21 g, 0.40 mmol) in H₂ O (2 mL) and THF (8 mL)was added lithium hydroxide monohydrate (0.051 g, 1.20 mmol) and stirredvigorously for six hours at room temperature. The reaction mixture wascooled to 0° C. and acidified to pH 2.0 with lN aqueous HCl. Theacidified reaction mixture was extracted with EtOAc (4 times) and thecombined organic layers were washed with brine, dried (MgSO₄), filteredand concentrated. The crude white solid was chromatographed on a silicagel column and eluted with 50% EtOAc in hexane with 0.25% CH₃ COOH addedto obtain title acid (0.20 g, 99%) as a white solid.

EXAMPLE 58[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzenepropanoicacid, methyl ester

A.[1S-(1α,2α,3α,4α)]-2-[2-2-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]propyl]-phenyl]ethanol]-7-oxabicyclo2.2.1]heptane-3-methanol

To a solution of[3-(2-bromophenyl)propyl]-dimethyl(1,1,2-trimethylpropyl)silyl]ether(6.61 g, 17.8 mmol) in 40 mL dry diethyl ether (Et₂ O) maintained at-78° C. was added 18.4 mL of a 1.7 M solution of t-C₄ H₉ Li in pentaneover a 25 minute period; the reaction was then stirred for an additional15 minutes at -78° C. and then allowed to come to 0° C. and stirred for3 minutes. The reaction mixture was then cooled to -78° C. and 25 mL ofdry THF was added followed by a solution of octahydro5,8-epoxy-1H-2-benzopyran-3-ol (1.25 g, 7.3 mmol) in 15 mL of dry THF;the mixture was allowed to stir at -78° C. for an additional 15 minutesand then warmed to 0° C. for 1 hour. The reaction was quenched with 3 mLof H₂ O, and then poured into H₂ O and extracted twice with EtOAc. Theorganic layers were combined, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to leave an oil. The crude product was purified byflash chromatography on 800 mL of LPS-1 silica gel using 1:1hexane/EtOAc and then EtOAc as the eluent. Isolation of product afforded2.98 g (90%) of title compound in the form of a clear oil.

[α]_(D) =+0.27° (c=22.3, CHCl₃)

TLC system 1:1 hexane/EtOAc (UV and Ce(SO₄)₂ detection) R_(f) titlecompound: 0.12.

B.[1S-(1α,2α,3α,4α)]-2-2-[2-[3-[[Dimethyl(1,1,2-trimethylpropyl)silyl]-oxy]propyl]phenyl]ethyl]-7-oxabicyclo-[2.2.1]heptane-3-methanol

A solution of Part A compound (2.8 g, 6.3 mmol) and 20% Pd(OH)₂ oncarbon (moist<50% H₂ O; 0.91 g, 33 wt %) in 70 mL of glacial acetic acidwas stirred vigorously under an atmosphere of hydrogen (balloon) at roomtemperature. After 24 hours reaction was still not complete, and anadditional 15 weight percent, of catalyst was added. After an additional24 hours the reaction was complete, and the mixture was filtered andconcentrated in vacuo. The residue was taken up in EtOAc and washedtwice with 1N NaOH followed by brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 2.74 g of a colorlessliquid. The crude product was flash chromatographed on 400 mL of LPS-1silica gel using 3:1 hexane/EtOAc for 3 L and then 1:1 hexane/EtOAc for1 L. Removal of solvents afforded 2.00 g of title compound (77%).

[α]_(D) =+9.28 (c=1.94, CHCl₃)

TLC system: 2:1 EtOAc/Hexane, R_(f) title compound: 0.4 (UV and Ce(SO₄)₂detection).

C.[1S-(1α,2α,3α,4α)]-2-[2-[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzenepropanoicacid, methyl ester

A solution of the Part B compound (2.21 g, 5.11 mmol) in 13 mL of 1:1pyridine-acetic anhydride was treated with N,N-dimethylamino pyridine(DMAP.) (0.12 g, 0.98 mmol) and then stirred at room temperature for 3hours. The reaction mixture was then concentrated in vacuo and theresidue partitioned between EtOAc and lN HCl. The organic layer wasseparated and washed with 1N NaOH followed by brine, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to yield a yellowliquid.

A solution of the crude acetate in 35 mL of reagent grade acetone waschilled to 0° C. and treated with Jones Reagent (2.6 M in Cr⁺⁶, 7 mL).The solution was stirred at room temperature for 2 hours, then 3 mL ofisopropyl alcohol (IPA) was added and the solution was allowed to stirfor 30 minutes. The green slurry was filtered through a Celite pad andconcentrated in vacuo. The residue was partitioned between H₂ O and Et₂O. The organic layer was separated and dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 3.0 g of a colorless oil.

The crude acid-acetate was stirred at room temperature in 60 mL of a 1:2solution of THF-1N NaOH for 3 hours. The reaction was cooled to 0° C.and quenched with 30 mL of 1N HCL, and then extracted four times withEt₂ O. The ethereal layers were combined and dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to yield 2.47 g of a yellowishliquid.

The crude acid-alcohol was stirred at 0° C. in 23 mL of acidic methanol(prepared by the addition of 1.1 mL of acetyl chloride to dry methanolat 0° C.), for 2 hours. The solution was concentrated in vacuo to yield1.47 g of a brown oil. The crude alcohol-ester was flash chromatographedon 200 mL of LPS-1 silica gel using EtOAc as the eluent. Removal ofsolvents in vacuo left 1.1 g (67%) of title compound in the form of atannish oil.

[α]_(D) =+17.0 (c=2.00, CHCl₃)

TLC system EtOAc R_(f) title compound: 0.45 (UV and Ce(SO₄)₂ detection)

D.[1S-(1α,2α,3α,4α)]-2-[2-[3-(Carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzenepropanoicacid, methyl ester

A solution of Part C compound (1.21 g, 3.8 mmol) in 12 mL of reagentacetone was chilled to 0° C. and treated with Jones Reagent (2.6 M inCr⁺⁶ 4.7 mL), and then stirred at room temperature for 2 hours. Then 2.5mL of IPA was added and the reaction was left to stir for an additional15 minutes. The resulting green slurry was filtered through a Celite padand then partitioned between H₂ O and Et₂ O. The aqueous layer wasseparated and then washed with another portion of Et₂ O. The organiclayers were combined, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to yield 1.2 g (95%) of title compound in the formof a greenish-yellow liquid.

[α]_(D) =+153.6 (c=7.26, CHCl₃)

TLC system EtOAc; R_(f) title compound: 0.39 (UV and Ce(SO₄)₂detection).

E.[1S-(1α,2α,3α,4α)]-2-[2-[3-[[[1-(Hydroxymethyl)-2-(amino-4-cyclohexyl-

butyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzenepropanoicacid, methyl ester

A solution of Part D ester (0.85 g, 2.56 mmol), 1-hydroxybenzotriazlehydrate (HOBt.H₂ O) (0.43 g, 2.55 mmol) and[1-aminoethane-2-ol][4-cyclohexylamino]carbonyl hydrochloride (0.71 g,2.55 mmol) in 18 mL of dry DMF (stirred over 4 A sieves) was cooled to0° C. and triethylamine (0.80 g, 7.89 mmol) was added. The solution wasstirred at 0° C. until dissolution was complete and then WSC (0.49 g,2.55 mmol) was added, and the solutionw as warmed to room temperatureand stirredovernight. The DMF was removed in vacuo and the residue wasdissolved in EtOAc. The solution was washed twice with 1N HCl, once with1N NaOH and once with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to yield 1.21 g of an off-white solid. The crudeproduct was chromatographed on 250 mL of LPS-1 silica gel using EtOAc asthe mobile phase. Removal of solvents in vacuo left 0.34 g of titlecompound in the form of a white solid.

[α]_(D) =-0.16 (c=0.69, CHCl₃)

TLC system: 4% CH₃ OH/CH₂ Cl₂ R_(f) title compound: 0.21 (UV andCe(SO₄)₂ detection).

F.[1S-(1α,2α,3α,4α)]2-[2-[3-[4,5-Dihydro-4-[(4-cyclohexylbutyl)amino]-carbonyl]-2-oxazolin]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzenepropanoicacid, methyl ester

To a stirred solution of Part E compound (0.38 g, 0.68 mmol) andN,N-diisopropyl ethyl amine (0.36 mL, 2.1 mmol) in 18 mL of dry CH₂ Cl₂(distilled over P₂ O₅) was added methanesulfonyl chloride (0.053 mL,0.68 mmol). After one hour the solution was concentrated in vacuo andthe residue was dissolved in 8 mL of reagent acetone; the solution wasthen treated with K₂ CO₃ (0.28 g, 2.0 mmol), and the solution was thenheated to reflux. After four hours the solution was filtered, the solidswashed with reagent acetone and solvents removed in vacuo9 to yield acolorless oil. The oil was purified by flash chromatography on 100 mL ofLPS-1 silica gel using 1% CH₃ OH in CH₂ Cl₂ ; removal of solvents invacuo left 0.34 g (92%) of title compound in the form of a yellowishoil.

[α]_(D) =167.4 (c=0.95, CHCl₃)

TLC system 4% CH₃ OH/CH₂ Cl₂ R_(f) title compound: 0.40 (UV and Ce(SO₄)₂detection).

G.[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]-benzenepropanoicacid, methyl ester

A solution of CuBr (0.23 g, 1.03 mmol) in mL of EtOAc was treated withDBU (0.29 mL, 1.93 mmol) and let stir at room temperature for 45minutes. Next a solution of Part F compound (0.26 g, 0.48 mmol) in 3 mLof CHCl₃ was added and the reaction mixture was stirred at roomtemperature. After 24 hours additional DBU (0.29 mL, 1.93 mmol) andCuBr₂ (0.23 g, 1.03 mmol) was added and the solution allowed to stir atroom temperature for an additional 48 hours. The reaction mixture wasdiluted with CHCl₃ and washed twice with a 1:1 NH₄ OH/NH₄ Cl solution;the organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to leave a reddish residue. The residue waspurified by flash chromatography on 100 mL of LPS-1 silica gel using 2:1hexane/EtOAc as the mobile phase. Removal of solvents in vacuo left0.101 g (40%) of title compound in the form of a colorless oil.

[α[_(D) =+36.8 (c=0.19, CHCl₃)

TLC system 2:1 Hexane/EtOAc R_(f) title compound: 0.10 (UV and Ce(SO₄)₂detection).

EXAMPLE 591S-(1α,2α,3α,4α)]-2-[-2-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2yl]ethyl]benzenepropanoicacid

A solution of Example 58 ester (0.0971 g, 0.18 mmol) in 5 mL of 4:1THF/H₂ O was treated with LiOH.H₂ O (0.0234 g, 0.56 mmol) and thenstirred at room temperature for 3.5 hours. The reaction mixture was thencooled to 0° C. and acidified to pH=2 with lN HCl, and then poured on toH₂ O and extracted four times with EtOAc. The organic layers werecombined, washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo to yield 0.0844 g (89%) of title acid as a clearoil.

¹³ C NMR; CDC13 24.2, 26.4, 26.7, 27.3, 29.2, 29.6, 29.8, 31.3, 33.3,35.1, 37.0, 37.5, 39.2, 47.2, 49.4, 79.5, 79.6, 126.4, 126.6, 128.8,129.3, 135.9, 137.8, 139.0, 141.0, 160.7, 164.0, 177.1.

TLC system: 0.25% CH₃ COOH in EtOAc R_(f) title acid: 0.32 (UV andCe(SO₄)₂ detection).

EXAMPLE 60[1S-(1α,2α,3α,4α)-2-[[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept--yl]methyl]benzoicacid, methyl ester[1S-(1α,2α,3α,4α)]-o-[2-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)phenyl]-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol(Product A) andlS-(1,2α,3α,4α)]-2-[4',4'-Dimethylspiro[isobenzofuran-1(3H),2'-oxazolidin-2-yl]]-7-oxabccyclo-[2.2.1]heptane-3-methanol(Product B)

To a stirred solution of 4,5-dihydro-4,4-dimethyl-2-phenyloxazole in 70mL of dry THF (7.22 g, 41.3 mmol, preparation is described by A.I.Meyers et al, in J. Org. Chem., 39, 2787 (1974)) at -45° C. under argonwas added 2.5M n-C₄ H₉ Li/hexane (15.4 mL, 38.5 mmol) dropwise over 10minutes. The mixture was stirred at -45° C. for 3.5 hours at which time(endo)octahydro-4,7-epoxyisobenzofuran-1-ol (2.15 g, 13.8 mmol) wasadded in one portion. This mixture was stirred at -45° C. for 1 hour andat room temperature for 15.5 hours. To a stirred saturated NH₄ Clsolution (40 mL) was added slowly mL of the above reaction mixture,which was then extracted with EtOAc (4×50 mL). The EtOAc extracts weredried (MgSO₄), filtered and concentrated in vacuo to give crude productA. The remaining reaction mixture was quenched by the addition ofsaturated NaHCO₃ solution and partitioned between 100 mL of saturatedNaHCO₃ solution and EtOAc (4×120 mL). The combined EtOAc extracts weredried (MgSO₄), filtered and concentrated in vacuo to give crude productB. The products A and B have an identical TLC. These two products werecombined and chromatographed on g of Merck silica gel 60 using 1.5 L ofeach and 2% CH₃ OH in CH₂ Cl₂ as eluant to give title Product A (2.26 g,45%) and (secondary Product B) (2.19 g, 44%).

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) title Product A, 0.38;Product B, 0.44; (Ce(SO₄)₂)

¹³ C NMR title Product A (67.5 MHz, CDCl ): δ 161.5, 145.4, 131.3,130.4, 126.9, 126.4, 124.9, 79.5, 78.1, 77.9, 68.2, 61.9, 50.7, 49.9,30.0, 29.3, 28.5, 28.1.

¹³ C NMR secondary Product B (67.5 MHz, CDCl₃): δ 143.2, 131.7, 127.680.7, 79.5, 79.1, 68.0, 62.8, 51.5, 29.8, 29.6, 28.1.

B.[1S-(1α,2α,3α,4α)]-2-[1,3-Dihydro-3-oxo-1-isobenzofuranyl]-7-oxabicyclo-2.2.1]heptane-3-methanol

To a stirred mixture of Part A diol (1.26 g, 3.81 mmol) in 5 mL of THFwas added 25 mL of 5% (aqueous) oxalic acid solution. This homogeneousmixture was stirred vigorously at room temperature for 75 hours anddiluted with 200 mL of saturated NaHCO₃ solution. This mixture wasextracted with EtOAc (4×250 mL). The combined EtOAc extracts were dried(MgSO₄), filtered and concentrated in vacuo to give 0.91 g (98%) oftitle lactone.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.40, Ce(SO₄)₂.

¹³ C NMR title lactone (67.5 MHz, CDCl₃) δ 170.4, 149.8, 134.3, 129.2,126.3, 125.6, 121.9, 79.3, 78.7, 75.6, 62.2, 49.9, 49.8, 30.4, 28.7.

C.1S-(1α,2α,3α,4α)]-2-[[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzoicacid, methyl ester

To a stirred mixture of Part B lactone (980 mg, 4.02 mmol) in 18 mL ofglacial acetic acid under argon was added 1.00 g of 20% Pd(OH)₂ oncarbon. The atmosphere was replaced with hydrogen by several vacuum-fillcycles. The reaction mixture was stirred vigorously for 4 days. Themixture was filtered through a 2" pad of Celite and the pad was rinsedwith acetic acid (HOAc) (3×30 mL). The fitrate was concentrated invacuo. This crude acid was dissolved in 100 mL of CH₃ OH. To thisstirred mixture was then added 1 mL of acetyl chloride (AcCl). Themixture was stirred at room temperature for 16 hours and concentrated invacuo. This was chromatographed on 45 g of Merck silica gel 60 usinghexane-EtOAc 2:3 as eluant to give 490 mg of title ester and 60 mg ofacid. The acid was again dissolved in mL of CH₃ OH and treated with 0.5mL of acetyl chloride. The mixture was stirred at room temperature for16 hours and concentrated in vacuo. The crude product waschromatographed on 25 g of Merck silica gel 60 using hexane-EtOAc 2:3 aseluant to give 80 mg of title ester. The total yield was 570 mg (51%).

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.50, Ce(SO₄)₂.

NOTE: The azaorthoester Part A secondary product was also hydrolyzed tolactone in 89% yield. But this lactone failed to react under thehydrogenation conditions.

¹³ C NMR title ester (67.5 MHz, CDCl ): δ 167.7, 3.8, 132.0, 131.7,131.2, 128.9, 126.1, 79.3, 79.1, 61.8, 51.9, 49.5, 47.9, 33.0, 29.7,29.2.

D.[1S-(1α,2α,3α,4α)]-2-[[3-[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a stirred solution of Part C ester (560 mg, 2.03 mmol) in 50 mL ofacetone at 0° C. under argon was added MnS04 treated Jones reagent(about 00 mg MnSO₄ dissolved in 100 mL of Jones reagent) until an orangered color persisted. The mixture was stirred at 0° C. for 20 minutes andat room temperature for 30 minutes. The mixture was quenched withisopropyl alcohol (IPA) and concentrated in vacuo. The crude acid waspartitioned between 50 mL of 3M (aqueous) NaHSO₃ solution and EtOAc(4×70 mL). The combined EtOAc extracts were dried (MgSO₄), filtered andconcentrated in vacuo to give 577 mg (98%) of the desired acid. To astirred mixture of acid (490 mg, 1.69 mmol), 1-hydroxybenzotriazole.H₂ O(290 mg, 1.69 mmol) and N-(4-cyclohexylbutyl)serinamide (4.09 mg, 1.69mmol) in 15 mL of DMF at 0° C. under argon was added (C₂ H₅)₃ N (0.47mL, 3.38 mmol). To this mixture was then addedethyl-3(3-dimethylamino)-propyl carbodiimide (324 mg, 1.69 mmol). Thereaction mixture was stirred at room temperature for 10 hours andconcentrated in vacuo. The crude product was dissolved in 300 mL ofEtOAc and washed with 0.2 N NaOH solution (2×60 mL), 1N HCl solution(2×60 mL) and saturated NaHCO₃ solution (1×60 mL). The EtOAc layer wasdried (MgSO₄), filtered and concentrated in vacuo. Purification waseffected by flash chromatography on 60 g of Merck silica gel 60 using 2%CH₃ OH in CH₂ Cl₂ as eluant to give 0.73 g (84%) of title alcohol.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.44, Ce(SO₄)₂.

⁻⁻ C NMR title alcohol (67.5 MHz, CDCl₃) δ 172.9, 170.8, 167.7, 142.6,132.2, 131.9, 131.3, 129.0, 126.5, 79.1, 78.0 62.8, 54.6, 53.6, 52.1,49.5, 39.5, 37.4, 36.9, 34.6, 33.2, 33.2, 29.7, 29.3, 28.9, 26.6, 26.3,26.3, 24.1.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzoicacid, methyl ester

To a stirred solution of Part D alcohol (730 mg, 1.42 mmol) anddiisopropyl ethyl amine (0.74 mL, 4.26 mmol) in 30 mL of dry CH₂ Cl₂under argon at 0° C. was added methanesulfonyl chloride (MsCl) (0.13 mL,1.70 mmol). This mixture was stirred at 0° C. for 30 minutes and at roomtemperature for 1 hour. The mixture was concentrated in vacuo anddiluted with 30 mL of acetone. To this mixture was added K₂ CO₃ (589 mg,4.26 mmol). The reaction mixture was refluxed for 4 hours and cooled toroom temperature. The precipitate was filtered off and rinsed withacetone (4×30 mL). The filtrate was concentrated in vacuo andchromatographed on 35 g of Merck silica gel 60 using hexane-EtOAc 1:2 aseluant to give 680 mg (97%) of title oxazoline.

TLC: silica gel, EtOAc, R_(f) 0.31, Ce(SO₄)₂

⁻⁻ C NMR title oxazoline (22.5 MHz, CDCl ): δ 171,6, 169.7, 142.7,132.2, 132.2, 131.4, 126.5, 78.9, 77.8, 70.5, 68.3, 51.9, 49.7, 47.1,39.1, 37.3, 37.0, 34.5, 33.2, 33.2, 29.7, 28.6, 26.6, 26.2, 26.2, 24.0.

F.[1S-(1α,2α,3α,4α)-2-[[3-[4-[[(4-Cyclo-hexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, methyl ester

To a stirred solution of Part E oxazoline (680 mg, 1.37 mmol) in 15 mLof dry CH₂ Cl₂ was added 1.32 g of NiO₂. The reaction mixture wasstirred vigorously at room temperature for 1 hour at which time 680 mgof NiO₂ was added. The reaction mixture was stirred at room temperaturefor 2 hours and again 680 mg of NiO₂ was added. The mixture was stirredat room temperature for 2.5 hours and one more portion of 340 mg of NiO₂was added. The mixture was stirred at room temperature for one more hourand then diluted with 120 mL of EtOAc, 30 mL of 3M NaHSO₃ solution and40 mL of lM sodium citrate solution. The mixture was stirred vigorouslyuntil all solids dissolved. The mixture was extracted with EtOAc (4×100mL). The combined EtOAc extracts were dried (MgSO₄), filtered andconcentrated in vacuo. This was chromatographed on 24 g of Merck silicagel 60 using hexane-EtOAc 2:1 as eluant to give 380 mg (56%) of titleoxazole.

TLC: silica gel, EtOAc, R_(f) 0.82, Ce(SO₄)2. ¹³ C NMR title oxazole(67.5 MHz, CDCL₃): δ 167.6, 164.0, 160.6, 142.1, 140.6, 136.1, 132.0,131.9, 131.3, 129.3, 126.4, 79.7, 78.4, 51.9, 50.4, 47.2, 39.1, 37.5,37.1, 35.0, 33.3, 33.3, 29.9, 29.8, 28.9, 26.7, 26.3, 26.3, 24.2.

EXAMPLE 61[1S-(1α,2α,3α,4α)-2-[[3-[4-[(Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzoicacid

To a stirred solution of Example 60 oxazole (103 mg, 0.21 mmol) in 2 mLof CH₃ OH and 2 mL of THF was added 0.5 mL of lN NaOH.solution. Themixture was stirred at room temperature for 3 hours at which time 0.5 mLof lN NaOH solution was added. This mixture was stirred at roomtemperature for 2 hours. To this mixture was added 83 mg of solid NaOH.The mixture was stirred at room temperature for 2.5 hours at which time70 mg of solid NaOH was added. The reaction mixture was stirred at roomtemperature for 15 hours and concentrated in vacuo. The crude acid waspartitioned between 30 mL of lN HCl solution (saturated with KCl) andEtOAc (4×40 mL). The combined EtOAc extracts were dried (MgSO₄),filtered and concentrated in vacuo. Purification was effected by flashchromatography on 12 g of Merck silica gel 60 using 4% CH₃ OH/CH₂ Cl₂ aseluant to give 62.5 mg (62%) of pure title acid.

TLC: silica gel, 6% CH₃ OH H/CH₂ Cl₂, R_(f) 0.50, Ce(SO₄)₂).

⁻⁻ C NMR title acid (67.5 MHz, CDCl₃): δ 164.5, 161.6, 145.3, 142.9,142.5, 140.9, 135.6, 131.9, 131.9, 126.5, 79.7, 78.4, 50.9, 47.3, 39.4,37.5, 37.1, 35.6, 33.3, 33.3, 29.8, 28.7, 26.7, 26.4, 26.4, 24.2.

EXAMPLE 62[1S-(1α,2α,3α,4α)]-2-[3-[4-[(Decylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of acid prepared in Example 2, PartJ in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (0.63 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalylchloride solution. The reaction was stirred until gas evolution ceased(about 30 minutes), then the mixture was concentrated in vacuo to givethe crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 98 mg (0.62 mMol, Aldrich) of n-decylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate/60 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica gel, 2:1 ethylacetate/hexane) to give 210 mg (0.40 mMol, 77%) of title ester as awhite solid.

EXAMPLE 63[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Decaylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid

To a mixture of 210 mg (0.40 mMol) of Example 62 ester in 8 mL distilledTHF/2 mL water was added 34 mg (0.80 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaciion was stirred vigorously for 4 hours, thenquenched by the addition of 1.6 mL (1.6 mMol) lM HCl. The mixture waspartitioned between 40 mL ethyl acetate/40 mL water. The ethyl acetatelayer was separated, dried (MgSO₄) and concentrated in vacuo to give 196mg (0.38 mMol, 96%) of title acid, SQ 34,607, as a white solid, mp145°-147° .

IR (KBr): 3413, 3130, 2926, 2854, 1709, 1649, 1604, 1518 cm⁻¹.

MS(CI): 511 (M-H)⁺.

OR: [α]_(D) =+16.1° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, ethyl acetate)=0.15, ammonium molybdate/cericsulfate and UV, homogeneous.

Analysis Calc'd for C₃₀ H₄₂ N₂ O₅ +0.10 H₂ O: C, 70.31; H, 8.30; N,5.47,

Found: C, 70.46; H, 8.48; N, 5.38

EXAMPLE 64[1S-(1α,2α,3α,4α)]-2-[[3-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]-hept-2-yl]methyl]benzeneaceticacid

A[1S-(1α,2α,3α,4α)]-α-[2-[2-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]ethyl]-phenyl]-7-oxabicyclo2.2.1]heptane-2,3-dimethanol

To a stirred mixture of Mg turning (4.67 g, 192 mmol) and few crystalsof iodine in 50 mL of dry THF at 65° C. under argon was added about 5%of a solution of Example 54, Part A bromide (16.5 g, 48.1 mmol) in 30 mLof dry THF. This mixture was heated at 65° C. for 20 minutes at whichtime the iodine color had dispersed. The remaining 95% of the bromidesolution was added dropwise over 20 minutes. The mixture was heated at65° C. for 1 hour and cooled to 0° C. To a stirred mixture of(endo)-octahydro-4,7-epoxyisobenzofuran-1-ol hemiacetal (5.00 g, 32.1mmol) in 40 mL of dry THF under argon at 0° C. was added 2.0 M solutionof C₂ H₅ MgBr in THF (14.4 mL, 28.8 mmol). This mixture was stirred at0° C. for 10 mintues at which time the above precooled (0° C.) Grignardsolution was added dropwise over 10 minutes. The reaction mixture wasstirred at room temperature for 22 hours and was quenched by theaddition of a solution of 10 g of NH₄ Cl in 35 mL of H₂ O. This mixturewas then combined with 250 g of anhydrous Na₂ SO₄ and diluted with 300mL of CH₂ Cl₂. The solid was filtered off and rinsed with CH₂ Cl₂ (4×60mL). The filtrate was concentrated in vacuo and partitioned between 300mL of saturated NH₄ Cl solution and EtOAc (4×400 mL). The EtOAc extractswere dried (MgSO₄), filtered and concentrated in vacuo. Purification waseffected by flash chromatography on 240 g of Merck silica gel 60 using1.2 L each of 1%, 2%, and 3% CH₃ OH in CH₂ Cl₂ as eluant to give 11.9 g(91%) of the title diol.

TLC: silica gel, 4% CH₃ OH H/CH₂ Cl₂, R_(f) 0.42, Ce(SO₄)₂.

B.[1S-(1α,2α,3α,4αa)]-2-[[3-[(Acetyl-oxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzeneethanol

To a stirred mixture of Part A diol (11.8 g, 28.1 mmol) in 180 mL ofacetic acid under argon was added 20% Pd(OH)₂ /C (2.4 g, 20% based onthe weight of Part A diol). The atmosphere was replaced with hydrogenand the mixture was stirred at room temperature for 24 hours. Thecatalyst was filtered off and rinsed with EtOAc (4×100 mL). The filtratewas diluted with 0.5 L of benzene and concentrated in vacuo to give thecrude alcohol. To a stirred mixture of this alcohol in 9.3 mL ofpyridine at 0° C. under argon was added acetic anhydride (4.08 mL, 43.2mmol) over 5 minutes. The mixture was stirred at room temperature for 16hours and diluted with 700 mL of ether. The mixture was washed with lNHCl solution (2×175 mL), saturated NaHCO₃ solution (2×150 mL) and brine(1×120 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to give crude acetate. To a stirred mixture ofthis acetate in 11 mL of dry THF under argon at room temperature wasadded 1M solution of (n-C₄ H₉)₄ NF in THF (25 mL, 25 mmol) over 10minutes. This mixture was stirred at room temperature for 17 hours anddiluted with 400 mL of EtOAc. The mixture was then washed with lN HClsolution (3×60 mL), saturated NaHCO₃ solution (1×60 mL) and brine (1×100mL). The organic layer was dried (MgSO₄), filtered and concentrated invacuo. Purification was effected by flash chromatography on 160 g ofMerck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 5.5 g(68%) of the title acetate alcohol.

TLC: silica gel, 4% CH₃ OH H/CH₂ Cl₂. R_(f) 0.48, Ce(SO₄)₂.

C.(lS-(1α,2α,3α,4α)]-2-[[3-[(Acetyl-oxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]-benzeneaceticacid, methyl ester

To a stirred mixture of Part B acetate alcohol (3.80 g, 13.2 mmol) in 60mL of dry CH₂ Cl₂ was added Dess-Martin oxidant (6.48 g, 14.5 mmol).This heterogeneous mixture was stirred at room temperature for 3 hoursand diluted with a solution of 100 mL of ether and 60 mL of saturatedNaHCO₃ solution. To this mixture was added 5 g of sodium thiosulfate.The mixture was stirred at room temperature for 5 minutes. The aqueouslayer was separated and extracted with ether (4×100 mL). The combinedorganic extracts were washed once with 60 mL of brine, dried (MgSO₄),filtered and concentrated in vacuo. The crude product was loaded on a 4"pad of Merck silica gel 60 in a 600 mL of fritted glass funnel andeluted with 250 mL of 4% CH₃ OH in CH₂ Cl₂ to give 3.69 g (98%) of purealdehyde.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.74, Ce(SO₄)₂.

To a stirred mixture of aldehyde (3.68 g 12.9 mmol) in 129 mL of B & JCH₃ OH H was added N-iodosuccinimide (7.24 g, 32.2 mmol), followed bythe immediate addition of K₂ CO₃ (4 45 g, 32.2 mmol). This mixture wasstirred in the dark at room temperature for 70 minutes and filteredthrough a 2" pad of Celite. The Celite pad was rinsed with CH₃ OH (3×40mL). The filtrate was concentrated in vacuo and diluted with 400 mL ofEtOAc. The resulting EtOAc solution was washed in lN HCl solution (2×30mL), saturated sodium thiosulfate solution (2×50 mL) and brine (1×50mL). The organic layer was dried (MgSO₄), filtered and concentrated invacuo. This was chromatographed on 120 g of Merck silica gel 60 using1.4 L each of 2:1 and 1:1 hexane-ether as eluants to give 2.30 g (57%)of title ester.

TLC: silic gel, 1:1 hexane-ether, R_(f) 0.44, Ce(SO₄)₂.

D.[1S-(1α,2α,3α,4αa)]-2-[3-(Carboxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzeneaceticacid, methyl ester

To a stirred mixture of Part C ester (2.27 g, 6.83 mmol) in 60 mL of B %J CH₃ OH under argon was added anhydrous K.sub. CO₃ (0.199 g, 1.37mmol). This mixture was stirred vigorously at room temperature for 2hours at which time 0.03 g of anhydrous K₂ CO₃ was added. The mixturewas stirred at room temperature for 1.5 hours and concentrated in vacuoto about 5 mL. This mixture was partitioned between 80 mL of saturatedNaHCO₃ solution and EtOAc (4×100 mL). The combined EtOAc extracts weredried (MgSO₄), filtered and concentrated in vacuo to give the crudealcohol. To a stirred mixture of this alcohol in 140 mL of acetone in acold water bath was added MnSO₄ treated Jones reagent (about 5 mL) untilan orange-red color persisted. This mixture was stirred at roomtemperature for 2 hours and quenched with IPA. The mixture wasconcentrated in vacuo and partitioned between 100 mL of 3M NaHSO₃solution and EtOAc (4×120 mL). The combined EtOAc extracts were washedwith brine (2×50 mL), dried (MgSO₄), filtered and concentrated in vacuoto give 2.08 g of title acid in a quantitative yield.

TLC: silica gel, 10% CH₃ OH/CH₂ Cl₂, R_(f) 0.36, Ce(SO₄)₂.

E.[1S-(1α,2α,3α,4α)]-2-[[3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxy-methyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzeneaceticacid, methyl ester

To a stirred mixture of Part D acid (100 g. 3.29 mmol),1-hydroxybenzotriazole monohydrate (0.56 g, 3.29 mmol) and Example lA,Part B amine.HCl (1.10 g, 3.95 mmol) in 30 mL of DMF under argon wasadded sequentially (C₂ H₅)₃ N (1.38 mL, 9.87 mmol) andethyl-3-(3-dimethylamino) propyl carbodiimide hydrochloride salt (30.69g, 3.62 mmol). This mixture was stirred at room temperature for 17 hoursand concentrated in vacuo. The crude product was diluted with 400 mL ofEtOAc and washed with 1N HCl solution (2×70 mL), 0.2 N NaOH solution(1×50 mL), saturated NaHCO₃ solution (1×50 mL), and brine (1×100 mL).The organic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was chromatographed on 140 g of Merck silica gel 60 using 4% CH₃ OHin CH₂ Cl₂ as eluant to give 1.35 g (78%) of title amide.

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.24, Ce(SO₄)₂.

F. [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-Cyclohexylbutyl)amino]carbonyl]-45-dihydro-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzeneaceticacid, methyl ester

To a stirred mixture of Part E amide (1.35 g, 2.56 mmol) in 30 mL ofCHCl₃ under argon at 0° C. was added sequentially diisopropylethyl amine(0.58 mL, 3.32 mmol) and methanesulfonyl chloride (0.24 mL, 3.07 mmol).The reaction mixture was stirred at 0° C. for 1 hour and at roomtemperature for 1 hour. This mixture was concentrated in vacuo anddiluted with 100 mL of acetone. To this mixture was added K₂ CO₃ (1.00g, 7.24 mmol). The mixture was refluxed gently under argon for 3 hoursand cooled to room temperature. The solid was filtered off and rinsedwith acetone (3×30 mL). The filtrate was concentrated in vacuo andchromatographed on 60 g of Merck silica gel 60 using 2% CH₃ OH n CH₂ Cl₂as eluant to give 1.23 g (94%) of title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.44, Ce(SO₄)₂.

G.1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid, methyl ester

To a stirred mixture of CuBr₂ (1.06 g, 4.74 mmol) in 12 mL of EtOAc wasadded DBU (1.42 mL, 9.47 mmol). This mixture was stirred at roomtemperature for 30 minutes at which time a solution of Part F oxazoline(1.15 g, 2.25 mmol) in 12 mL of CHCl₃ was added. This mixture wasstirred at room temperature for 17 hours. To this mixture was addedCuBr₂ (0.53 g, 2.37 mmol) and DBU (0.70 mL, 4.73 mmol). This mixture wasstirred vigorously at room temperature for 8 hours at which time againCuBr₂ g, (0.53 g, 2.37 mmol) and DBU (0.34 mL, 2.36 mmol) was added. Thereaction mixture was stirred at room temperature for another 18 hoursand poured into a solution of 200 mL of EtOAc and 200 mL of 1:1concentrated NH₄ OH solution and saturated NH₄ Cl solution. The aqueouslayer was separated and extracted with EtOAc (2×250 mL). The combinedorganic extracts were washed once with 100 mL of brine, dried (MgSO₄),filtered and concentrated in vacuo. Purification was effected by flashchromatography on 65 g of Merck silica gel 60 using 2% CH₃ OH as eluantto give 370 mg (32%) of title oxazole.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.52, Ce(SO₄)₂.

EXAMPLE 65[1S-(1α,2α,3α,4α)]-2-[[3-[[(4-Cyclohexylbutyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzeneaceticacid

To a stirred mixture of Example 64 oxazole (360 mg, 0.71 mmol) in 15 mLof freshly distilled THF and 3.50 mL of H₂ O was added LiOH.H₂ O (89.2mg, 2.13 mmol). This mixture was stirred at room temperature vigorouslyfor 6.5 hours and acidified tp pH 2 by the addition of lN HCl solution.This mixture was diluted with 15 mL of H₂ O and extracted with EtOAc(4×30 mL). The combined EtOAc extracts were washed with brine (2×15 mL),dried (MgSO₄), filtered and concentrated in vacuo. This wasrecrystallized in 30 mL of 8:1 hexane-EtOAc at room temperature to give280 mg (80%) of title pure acid as a solid, m.p. 130°-132° C.

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.10, Ce(SO₄)₂).

⁻⁻ C NMR (67.5 MHz, CDCl₃): δ 174.9, 163,9, 160.8, 141.1, 138.5, 135.8,132.6, 130.9, 129.7, 127.5, 127.5, 126.6, 79.6, 78.6, 49.6, 46.9, 39.2,%8.3, 37.5, 37.0, 33.3, 33.3, 32.8, 29.8, 29.7, 28.8, 26.7, 26.3, 26.3,24.2.

EXAMPLE 66[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Cyclohexylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol, L223-88-23) of Example 2, Part Jacid in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small dropof DMF, followed by 310 μL (0.63 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalylchloride solution. The reaction was stirred at room temperature untilgas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo to give the crude acid chloride as a pale yellowsolid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 62 mg (0.62 mMol, Aldrich) of cyclohexylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate/60 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica, 1:2 ethyl acetate/hexane) to give 220 mg (0.47 mMol, 91%) of title ester as a white solid.

EXAMPLE 67[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Cyclohexylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid

To a mixture of 220 mg (0.47 mMol) of Example 66 ester in 8 mL distilledTHF/2 mL water was added 40 mg (0.94 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 4 hours at roomtemperature, then quenched by the addition of 1.8 mL (1.8 mMol) 1M HCl.The mixture was partitioned between 40 mL ethyl acetate/40 mL water. Theethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give 210 mg (0.46 mMol, 98%) of title acid, SQ 34,614, as awhite form m.p. 58°-62°.

IR (KBr): 3400, 3121, 2933, 2854, 1728, 1645, 1601 cm⁻¹.

MS(CI): 453 (M+H)⁺.

OR: [α]_(D) =+14.9° (c=1.0 in chloroform)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.37, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₃ H₂₈ N₂ O₅ +0.45 mol H₂ O: C, 67.78; H, 7.20; N,6.08;

Found: C, 67.82; H, 7.27; N, 6.04

EXAMPLE 68[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-Methylethyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of Example 2, Part J acid in 20 mLdry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop of DMF,followed by 310 μL (0.63 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalyl chloridesolution. The reaction was stirred at room temperature until gasevolution ceased (about 30 minutes), then the mixture was concentratedin vacuo to give the crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 37 mg (0.62 mMol, Aldrich) of isopropylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate/60 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica gel, 2:1 ethylacetate/hexane) to give 112 mg (0.26 mMol, 51% of title ester as a whitesolid.

EXAMPLE 69[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-Methylethyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid

To a mixture of 112 mg (0.26 mMol) of Example 68 ester in 8 mL distilledTHF/2 mL water was added 22 mg (0.53 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 3 hours at roomtemperature, then quenched by the addition of 1.1 mL (1.1 mMol) 1M HCl.The mixture was partitioned between 40 mL ethyl acetate/40 mL water. Theethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give 100 mg (0.24 mMol, 92%) of title acid as a white foam, mp57°-63°.

IR (KBr): 3431, 3416, 2972, 1716, 1651, 1602 cm⁻¹.

MS(CI): 413 (M+H)⁺.

OR: [α]_(D) =+16.8° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.32, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₃ H₂₈ N₂ O₅ +0.59 H₂ O: C, 65.29; H, 6.95; N,6.62;

Found: C, 65.49; H, 7.05; N, 6.42

EXAMPLE 70[1S-(1α,2α,3α,4α)-2-[[3-[4-[[(8-Cyclohexyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A. 4-Cyclohexane-1-butanal

A solution of 3.06 mL (4.45 g, 35.0 mmol) of oxalyl chloride in 150 mLof dry methylene chloride was stirred under argon at -60° C. in anacetone and dry ice bath. A solution of 5.0 mL (5.99 g, 76.7 mmol) ofmethylene chloride was added slowly and the resulting mixture wasstirred at -60° C. for ten minutes before 5.0 g (31.9 mmol) of4-cyclohexyl-1-butanol was added slowly. After 20 minutes 22.23 mmol(16.13 g 159.5 mmol) of triethylamine was added slowly at -60° C. Thecooling bath was then removed and the reaction was warmed up to roomtemperature. 17 mL of water was added and after stirring, the two layerswere separated. The aqueous layer was extracted twice more withmethylene chloride (50 mL). The organic layers were combined, washedwith brine, dried over MgSO₄, and concentrated to obtain title aldehydein the form of a yellow semisolid 4.63 g (94%).

B. (3-Carboxypropyl)triphenylphosphonium bromide

A solid mixture of 4-bromobutyric acid (100 g, 0.60 mol) andtriphenylphosphine (157.1 g, 0.60 mol) was reacted at 140° C. (oil bathtemperature) under argon for 3 hours. When heat was first applied, bothsolid starting materials melted to form a homogeneous solution. After afew minutes of heating, extensive precipitation occurred. After coolingto room temperature, a rock-hard solid was broken up, suspended in 250mL of refluxing chloroform under argon, and diluted with 800 mL ofether. Stirring at room temperature was carried out for 30 minutes. Thesuspension was cooled to 0° C. (ice bath temperature), and the productwas collected by filtration and washed with ether. Yield: 218.12 g.

C. (Z)-8-Cyclohexyl-4-octenoic acid

To a stirred solution of 17.77 g (41.49 mmol) of Part B acid in 75 mLTHF at 0° C. under argon, was added slowly 42 mL (75.2 mmol) ofK-t-amyl-alcoholate. After the reaction mixture was stirred for 1/2hour, 4.0 g (25.9 mmol) of Part A aldehyde was added as a solution in2.5 mL of CHCl₃. The reaction mixture was stirred for 24 hours at roomtemperature. The reaction was quenched by the addition of 18 mL of CH₃CO₂ H and concentrated on a roto evaporator. Residual CH₃ CO₂ H wasremoved by twice adding toluene and concentrating. The residue wasextracted with 100 mL ethyl acetate, the organic layers separated andthe aqueous layer extracted twice more (100 mL each). The organic layerswere combined, washed with brine, dried over MgSO₄, and concentrated toobtain an oil. The oil was chromatographed eluting with a gradient ofhexane and ethyl acetate (80:20-70:30) containing 0.5% CH₃ CO₂ H toobtain 5.8 g (100%) of title acid in the form of an orange oil.

R_(f) =0.6 in 1:1 hexane-EtOAc with 0.5% AcOH.

¹³ C NMR (67.8 MHz, CDCl₃): δ 179.7, 131.9, 126.9, 37.6, 37.1, 34.2,33.3, 27.4, 26.9, 26.7, 26.4, 22.5.

D. Cyclohexaneoctanoic acid

A solution of 5.50 g (25.8 mmol) of Part C acid in 30 mL of CH₃ CO₂ Hwas stirred at room temperature under argon. A hydrogen balloon wasattached, and the reaction mixture was stirred at room temperature fortwo days. The reaction mixture was filtered through a celite pad and thefilter cake was washed with methylene chloride. The filtrate wasconcentrated to obtain 5.20 g (90%) of title acid in the form of abrownish oil.

¹³ C NMR (67.8 MHz, CDCl₃): δ 171.0, 37.6, 37.6, 37.4, 34.1, 33.4, 29.7,29.2, 29.0, 26.7, 26.4, 26.0, 24.7.

E. Cyclohexaneoctanamide

To a solution of 5.1 g (22.5 mmol) of Part D acid in 20 mL of dry CH₂Cl₂ at 0° C. under argon was added dropwise 9.8 mL (14.3 g, 113 mmol) ofoxalyl chloride. The ice bath was removed, and the reaction mixture waswarmed to room temperature and stirred for 18 hours. The reactionmixture was concentrated, toluene (100 mL) was added, and the mixturewas concentrated again. This process was repeated once more. To theresidue, 5 mL of 9M methanolic ammonia was added and this was stirred atroom temperature for 21/2 days. To this 100 mL ethyl acetate and 20 mLwater were added and the two layers were separated. The aqueous layerwas extracted twice more with ethyl acetate (100 mL each). The organiclayers were combined, washed with brine, dried over MgSO₄, andconcentrated to obtain a brown oil. This was crystallized by theaddition of hexane. A small amount, 0.46 g (9%) of title amide in theform of a tan solid was obtained.

R_(f) =0.48 in 0.5% NH₄ OH/EtOAc.

⁻⁻ C NMR(67.8 MHz, CDCl₃): δ 176.0, 37.4, 37.2, 35.6, 33.2, 29.6, 29.1,29.0, 26.6, 26.2, 25.3.

F. Cyclohexaneoctanamine

To a solution of 0.46 g (2.04 mmol) of Part E amide in 50 mL of ether at0° C. under argon was added slowly 0.09 g (2.24 mmol) of lithiumaluminum hydride, and the reaction was warmed to room temperature. Aftertwo hours the reaction mixture was quenched with 0.09 mL of water, then0.09 mL of 15% aqueous NaOH, followed by 0.27 mL of water. Afterstirring for 15 minutes, the precipitate was filtered, and the filtratewas concentrated to obtain a semi-solid. This was chromatographed using0.5% concentrated aqueous NH₃ in ethyl acetate to obtain 0.21 g (49%) oftitle amine in the form of a yellow oil.

R_(f) =0.41 in 0.5% NH₄ OH/EtOAc.

⁻⁻ C NMR(67.8 MHz, CDCl₃) δ 42.1, 37.6, 37.5, 33.7, 33.4, 29.9, 29.6,29.4, 26.8, 26.7, 26.4.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(8-Cyclo-hexyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid, methyl ester

To a solution of (0.21 g, 0.99 mmol) Part F amine in 5 mL of chloroformunder argon at 0° C., was added (0.14 mL, 0.10 g, 0.99 mmol)triethylamine and (0.20 g, 0.49 mmol) Example 2, Part J acid. Themixture was stirred at room temperature for 18 hours, then diluted with20 mL of chloroform and 5 mL of water. The organic layer was separated,and the aqueous layer was extracted with 20 mL of chloroform twice. Theorganic layers were combined, washed with brine over MgSO₄, andconcentrated to obtain title compound in the form of a white solid 0.22g (77%).

R_(f) =0.8 in EtOAc.

¹³ C NMR (67.8 MHz, CDCl₃) δ 173.0, 163.7, 160.4, 140.4, 138.4, 137.8,136.1, 129.6, 128.9, 126.6, 126.4, 79.6, 78.6, 51.5, 49.9, 46.9, 39.0,37.6, 37.4, 34.8, 33.3, 32.3, 29.8, 29.6, 29.5, 29.2, 28.8, 27.6, 26.8,26.4.

EXAMPLE 71[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(8-Cyclohexyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-y1]methyl]benzenepropanoicacid

A solution of (0.22 g, 0.38 mmol) of Example 70 ester in 1 mL of 1Naqueous NaOH, 3 mL of THF, and 2 mL water was stirred for 18 hours.

After acidification to pH 1.5 with 10% HCl, 25 mL of EtOAc was added,and the organic layer was separated. The aqueous layer was extractedtwice with 25 mL EtOAc. The organic layers were combined, washed withbrine, dried over MgSO₄, and concentrated in vacuo to obtain 0.18 g ofsolid.

This was crystallized from chloroform and hexane to obtain 0.18 g (86%)of title acid in the form of a solid.

R_(f) =0.59 in (0.5% acetic acid in ethyl acetate; UV, Ce(SO₄)₂, m.p.148°-149°.

[α]°_(D) =+38.4 in CH₃ OH at c 0.50 g/100 mL.

EXAMPLE 72[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethvl]benzoicacid, methyl ester

A. 3-[[Dimethyl(1,1,2-trimethylpropyl)-silyl]oxy]benzene bromide

To a stirred solution of 3-bromophenyl alcohol (5.0 g, 26.7 mmol) andtriethylamine (3.25 g, 32.1 mmol) in anhydrous CH₂ Cl₂ (125 mL) at roomtemperature under argon was added dropwise dimethylthexyl-silylchloride(5.26 g, 29.4 mmol). After 1.5 hours, 4-dimethylaminopyridine (0.50 g)was added and the stirring was continued for an additional 3 hours. Thereaction mixture was diluted with hexane (200 mL) and the precipitatewas filtered off. The filtrate was concentrated, partitioned betweenhexane (200 mL) and lN aqueous HCl (3×40 mL), and the organic layer waswashed with saturated aqueous NaHCO₃ (2×40 mL). The organic layer wasdried (MgSO₄), filtered and concentrated to yield title bromide (8.01 g,91%).

B.[1S-(1α,2α,3α,4α)]-o-[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]phenyl]-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-heptane-2-ethanol

To a solution of Part A bromide (5.88 g, 16.9 mmol) under argon inanhydrous ether (40 mL) at -78° C. was added t-butyllithium (17.8 mL,1.70M solution in pentane) over fifteen minutes, and the the mixture wasstirred for an additional 30 minutes at 0° C. The reaction solution wascooled to -78° C. and anhydrous THF (40 mL) was added.(endo)-Octahydro-5,8-epoxy-1H-benzopyran-3-ol (1.20 g, 7.10 mmol)dissolved in anhydrous THF (50 mL) was added dropwise and stirred forfifteen minutes at -78° C. A white precipitate formed. The reactionmixture was then warmed to 0° C. for one hour and quenched with water(3.0 mL). The aqueous mixture was extracted with EtOAc (2 times) and thecombined extracts were dried (MgSO₄), filtered and concentrated to givea yellow oil. The crude product was chromatographed on a silica gelcolumn and eluted with 50-100% EtOAc in hexane to obtain title compound(1.47 g, 49%) as a white foam.

C.[1S-(1α,2α,3α,4α)]-3-1-(Acetyloxy)-2-[3-(acetyloxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]ethyl]benzoicacid, methyl ester

To Part B compound (1.47 g, 3.49 mmol) in pyridine (1.70 mL) under argonat 0° C. was added acetic anhydride (1.07 g, 10.5 mmol) over tenminutes. The mixture was stirred at 0° C. for one hour, then at roomtemperature for sixteen hours. The reaction mixture was diluted withether (10 mL) and washed with lN aqueous HCl (3×25 mL). The ether layerwas dried (MgSO₄), filtered and concentrated. The residue was dissolvedin acetone (25 mL) and treated with Jones Reagent until the orange colorpersisted. The reaction mixture was stirred for four hours at roomtemperature, then quenched with excess IPA, concentrated and partitionedbetween water (30 mL) and EtOAc (3×30 mL). The combined organic layerswere washed with H₂ O, dried (MgSO₄), filtered and concentrated. Theresidue was dissolved in ether (30 mL) and treated with excess etherealdiazomethane at 0° C. for ten minutes. The reaction mixture wasconcentrated and chromatographed on a silica gel column and eluted with10-25% EtOAc-hexane to give title compound (1.22 g, 76%) as a viscous,colorless oil.

D.[1S-(1a,2α,3α,4α)]-3-[2-[3-(Acetyl-oxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-ethyl]benzoicacid, methyl ester

To a stirred solution of Part C compound (1.22 g, 3.12 mmol) in methylacetate (25 mL) under argon was added 70% aqueous HClO₄ (0.60 mL) and10% Pd/C (0.13 g). The atmosphere was replaced with H₂ from a H₂ filledballoon by several vacuum-fill cycles. The reaction mixture was stirredvigorously for 4 hours before the catalyst was filtered off through abed of anhydrous MgSO₄. The solids were rinsed well with EtOAc. Thefiltrate was concentrated to 1/2 its original volume and then was washedwith saturated aqueous NH₄ Cl, saturated aqueous KHCO₃, and brine. Theorganic layer was dried (MgSO₄), filtered and concentrated to give titlecompound (0.84 g, 81%) as a viscous, colorless oil.

E.[1S-(1α,2α,3α,4α)]-3-[2-[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-ethyl]benzoicacid, methyl ester

To Part C compound (0.80 g, 2.40 mL) in methanol (10 mL) and acetone (30mL) was added finely crushed K₂ CO₃ and stirred for 4 hours at 0° C. H₂O was added to the reaction mixture before the organic solvents wereremoved under reduced pressure. The aqueous layer was extracted withEtOAc (3 times), dried (MgSO₄), filtered and concentrated to give crudetitle compound (1.01 g) as a viscous oil. The alcohol was taken on tothe next step without further purification.

F. [1S-(1α,2α,3α,4α)]-3-[2-[3-Carboxy-7-acid, methyl ester

Part E compound (0.73 g, 2.52 mmol) in acetone (20 mL) at 0° C. underargon was treated with Jones Reagent until the orange color persisted.The reaction mixture was stirred while warming to room temperature. Onehour after the ice bath was removed the excess Jones Reagent wasdestroyed by the addition of IPA. After concentration the reactionmixture was partitioned between 3M aqueous NaHSO₃ and EtOAc (3 times).The combined organic layers were dried (MgSO₄), filtered andconcentrated to obtain title compound (0.40 g, 80%) as a whitecrystalline solid.

G.[1S-(1α,2α,3α,4α)]-3-[2-[3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzoicacid, methyl ester

Part F compound (0.40 g, 1.45 mmol), 1-hydroxybenzotriazole hydrate(0.25 g, 1.45 mmol), Example 1A, Part B amine HCl (0.40 g, 1.45 mmol)and DMF (10 mL) were combined under argon at 0° C. Triethylamine (0.44g, 4.34 mmol) was added and stirred for 25 minutes.1-(3-Dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.28 g,1.45 mmol) was added and the reaction mixture was stirred for sixteenhours while warming to room temperature. The reaction mixture wasdiluted with EtOAc, washed with 1N aqueous HCl (2 times), dilutedaqueous NaOH (2 times) and saturated aqueous KHCO₃. The organic layerwas dried (MgSO₄), filtered and concentrated to obtain title compound(0.50 g, 65%) as a white solid.

H.[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]ethyl]benzoicacid, methyl ester

To a stirred solution of Part G compound (0.50 g, 0.95 mmol) andN,N-diisopropylethylamine (0.37 g, 2.84 mmol) in CH₂ Cl₂ (25 mL) at 0°C. under argon was added methanesulfonyl chloride (0.11 g, 0.96 mmol)and stirred for one hour while warming to room temperture. The reactionsolution was concentrated and the residue was diluted with acetone (25mL). Finely powdered K₂ CO₃ (0.39 g, 2.84 mL) was added and the reactionmixture was refluxed for 21/2 hours. The reaction mixture was cooled toroom temperature, filtered and concentrated. The crude product waschromatographed on a silica gel column and eluted with 50% EtOAc inhexane to obtain title compound (0.48 g, 100° %) as a white solid.

I.[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzoicacid, methyl ester

To copper (II) bromide (0.44 g, 1.97 mmol) in EtOAc (3 mL) was added DBU(0.57 g, 3.76 mmol) and stirred for 30 mintues at room temperature. PartH compound (0.48 g, 0.94 mmol) dissolved in CHCl₃ (3 mL) was addeddropwise and stirred for 22 hours at room temperature. The reactionsolution was poured into a 1:1 aqueous NH₄ Cl:NH₄ OH mixture andextracted with EtOAc (2 times). The combined organic extracts were dried(MgSO₄), filtered and concentrated. The crude product waschromatographed on a silica gel column and eluted with 20-50% EtOAc inhexane to obtain title ester (0.23 g 48%) as a white solid.

EXAMPLE 73

[1S-(1α,2α,3α,4α)-3-2-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzoicacid

To Example 72 ester (0.23 g 0.45 mmol) in H₂ O (2 mL) and THF (8 mL) wasadded lithium hydroxide monohydrate (0.06 g, 1.36 mmol) and stirredvigorously for 18 hours at room temperature. The reaction mixture wascooled to 0° C. and acidified to pH 2.0 with 1N aqueous HCl. Theacidified reaction mixture was extracted with EtOAc (4 times) and thecombined organic layers were washed with brine, dried (MgSO₄), filteredand eluted with 50% EtOAc in hexane with 0.25% acetic acid added toobtain title acid (0.20 g, 91%) as a white solid. 1H (270 MHz, CDCl₃): δ8.96 (br s, 1H), 8.20 (s, 1H), 7.91 (d, 1H)™, 7.82 (s, 1H), 7.41-7.21(m, 2H), 7.09 (t, 1H), 4.90 (s, 1H), 4.55 (s, 1H), 3.48-3.23 (m, 3H),2.73-2.42 (m, 2H), 2.30-2.18 (m, 1H), 1.93-0.71 (m, 23H).

¹³ C (67.8 MHz, CDCl₃): δ 170.5, 164.0, 160.7, 141.6, 141.0, 135.9,133.4, 130.0, 129.9, 128.5, 127.9, 79.5, 48.9, 47.1, 39.2, 37.5, 37.0,34.3, 33.3, 31.7, 29.8, 29.5, 29.2, 26.6, 26.3, 24.2.

EXAMPLE 74[1S-(1α,2α,3α,4α)]-[2-[3-[4-[[[4-[4-(Methylthio-phenyl]butyl]aminocarbonyl]-2-oxazolyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester A. (E)-3-[4-(Methylthio)phenyl]-2-propanoic acid,methyl ester

A slurry of 6.00 g (39.5 mMol, Aldrich) of p-(methylthio)benzaldehyde,and 13.8 g (41.3 mMol, Aldrich) of methyl(triphenylphosphoranylidene)-acetate in 60 mL of dry THF (distilled fromsodium/ benzophenone ketyl) was stirred at room temperature for 18hours. The resulting homogeneous solution was concentrated in vacuo togive a solid. The crude material was purified by flash chromatography(Merck silica, 22×5.0 cm, methylene chloride load then 1:5 ethylacetate/hexane elution) to afford 6.53 g (31.4 mMol, 79%) of titleacrylate as a white solid, mp 89°-91°.

B. 4-(Methylthio)benzenepropanoic acid, methyl ester

A mixture of 1.00 g (4.81 mMol) of Part A acrylate and 2.00 g of 10%palladium on activated carbon catalyst (Aldrich) in 75 mL of reagentethyl acetate was shaken under an atmosphere of hydrogen (50 psi) on aParr apparatus for 18 hours. The reaction was filtered on a Buchnerfunnel then passed through a 4 μM polycarbonate membrane. The filtratewas concentrated in vacuo to give 1.00 g (4.76 mMol, 99%) of title esteras a colorless oil.

C. 4-(Methylthio)benzenepropanol

To a solution of 3.05 g (14.5 mMol) of Part B ester in 25 mL of dry THF(distilled from sodium/ benzophenone ketyl) cooled in an ice bath wasadded 650 mg (29.5 mMol, Alfa) of lithium borohydride. The reactionmixture was warmed to room temperature, stirred for 16 hours then cooledin an ice bath and quenched by slow addition of 100 mL of lM aqueous HClsolution. The resulting mixture was stirred for 10 minutes thenextracted with two-50 mL portions of ethyl acetate. The organic extractswere combined, washed with 100 mL of 1M aqueous NaOH solution, 25 mL ofbrine, dried (magnesium sulfate) and concentrated in vacuo to give anoil. The crude material was purified by flash chromatography (Mercksilica, 12×5.0 cm, 2:1 ethyl acetate/hexane) to yield 2.31 g (12.7 mMol,88%) of title alcohol as a colorless oil.

D. 4-(Methylthio)benzenebutanenitrile

To a solution of 2.26 g (12.4 mMol) of Part C alcohol in 15 mL of drymethylene chloride (distilled from phosphorous pentoxide) was added atroom temperature 1.56 g (13.6 mMol, Aldrich) of methanesulfonyl chloridethen 1.3 mL (16 mMol, Burdick and Jackson) of pyridine. The reactionmixture was stirred for 18 hours (TLC analysis showed about 20%unreacted starting materiaL) then an additional 0.50 g (4.4 mMol) ofmethanesulfonyl chloride and 0.40 mL (5.0 mMol) of pyridine were added.After 4 hours 60 mL of ethyl acetate was added to the reaction and theresulting slurry washed successively with two-25 mL portions of 1Maqueous HCl solution, 25 mL of saturated sodium bicarbonate solutionthen 25 mL of brine, dried (magnesium sulfate) and concentrated in vacuoto give the crude mesylate as an oil.

A mixture of the crude mesylate and 1.62 g (24.9 mMol, Mallinckrodt) ofpotassium cyanide in 20 mL of DMSO (Burdick and Jackson) was heated to75° for 2 hours. The resulting orange-brown semisolid was cooled to roomtemperature and partitioned between 100 mL of water and 75 mL of ethylacetate. The organic layer was separated, washed with two-100 mLportions of water, 25 mL of brine, dried (magnesium sulfate) andconcentrated in vacuo to give an oil. The crude oil was purified byflash chromatography (Merck silica gel, 12×5.0 cm, 1:4 ethylacetate/hexane) to afford 1.30 g (6.80 mMol, 55%) of title nitrile as acolorless oil.

E. 4-(Methylthio)benzenebutanamine, monohydrochloride

To a solution of 1.18 g (6.18 mMol) of Part D nitrile in 10 mL of dryether (distilled from sodium/benzophenone ketyl) cooled in an ice bathwas added 260 mg (6.84 mMol, Aldrich) of lithium aluminum hydride. Thereaction mixture was stirred at 0° for 15 minutes then at roomtemperature for 2.5 hours. The resulting solution was re-cooled in anice bath then quenched by slow, successive addition of 0.25 mL of water,0.25 mL of lM aqueous NaOH solution then 0.75 mL of water. The reactionwas warmed to room temperature, stirred for 15 minutes then theresulting slurry was filtered. The filtrate ws concentrated in vacuo togive the crude amine as an oil. The hydrochloride was obtained byaddition of 20 mL of ice-cold acidic methanol (prepared from 1 mL ofacetyl chloride to 20 mL of cold methanol) to the crude amine. Theresulting solution was concentrated in vacuo to give 1.13 g of crudeamine hydrochloride. The crude material was purified byrecrystallization (methanol/ether) to afford 689 mg (48%) of title aminehydrochloride as a white solid, mp 165° (softens).

F.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-[4-Methylthiophenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, methyl ester

To a solution of 500 mg (1.30 mMol) of acid prepared as described inExample 2, Part J in 6 mL of dry methylene chloride (distilled fromphosphorous pentoxide) was added at room temperature a small drop of DMFthen 135 μL (1.54 mMol, Aldrich) of oxalyl chloride. The reactionmixture was stirred until gas evolution ceased, 30 minutes, then thesolution was concentrated in vacuo to give the crude acid chloride as apale yellow solid.

To a solution of the crude acid chloride in 5 mL of dry methylenechloride, cooled in an ice bath, was added 362 mg (1.56 mMol) of Part Eamine hydrochloride then 400 μL (2.9 mMol, distilled from calciumhydride) of triethylamine. The reaction mixture was stirred for 30minutes then partitioned between 20 mL of ethyl acetate and 20 mL of lMaqueous HCl solution. The organic layer was separated, dried (magnesiumsulfate) and concentrated in vacuo to give a solid. The crude solid waspurified by flash chromatography (Merck silica, 12×3.0 cm, methylenechloride load then 2:1 ethyl acetate/hexane elution) to afford 600 mg(1.07 mMol, 82%) of title ester as a white solid.

EXAMPLE 75[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-[4-Methylthio-phenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabi-cvclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A mixture of 200 mg (0.36 mMol) of Example 74 ester and 30 mg (0.71mmol, Aldrich) of lithium hydroxide monohydrate in 3 mL of 2:1 THF/waterwas stirred rapidly at room temperature for 2 hours then acidified byaddition of 1.5 mL of 1M aqueous HCl solution. The mixture waspartitioned between 15 mL of ethyl acetate and 15 mL of water. Theorganic layer was separated, dried (magnesium sulfate) and concentratedin vacuo to give a solid. The crude material was purified byrecrystallization (acetonitrile/ethyl acetate) to afford 158 mg (0.29mMol, 80%) of title acid as a white solid, mp 155°-158°.

IR(KBr): 3441 (broad), 1723, 1643, 1602, 1523, 1105 cm⁻¹.

MS(CI): 549 (M+H)⁺.

OR: [α]_(D) =+17° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.51, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₁ H₃₆ N₂ O₅ S: C, 67.86; H, 6.61; N, 5.11; S,5.84.,

Found: C, 68.13; H, 6.80; N, 5.05; S, 5.87.

EXAMPLE 76[1S-(lo,2α,3α,4α)]-[2-[[3-[4-[[[4-[4-(Methylsul-fonylphenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 1.08 g (1.76 mMol, MW 615, Alfa) of oxonemonopersulfate in 4 mL of water was added rapidly a solution of 330 mg(0.59 mMol) of Example 74 ester in 8 mL of 1:1 methanol/THF (mildlyexothermic). The reaction mixture was stirred for 30 minutes thenpartitioned between 40 mL of water and 25 mL of ethyl acetate. Theorganic layer was separated and the aqueous layer was extracted with anadditional 25 mL of ethyl acetate. The organic extracts were combined,dried (magnesium sulfate) and concentrated in vacuo to give an oil. Thecrude oil was purified by flash chromatography (Merck silica, 15×3.0 cm,methylene chloride load the ethyl acetate elution) to afford 313 mg(0.54 mMol, 91%) of title sulfone as a white foam.

EXAMPLE 77[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[[4-[4-(Methylsulfon-ylphenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A solution of 305 mg (0.51 mMol) of Example 76 ester and 45 mg (1.1mMol, Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/waterwas stirred rapidly at room temperature for 1.5 hours. The reactionmixture was acidified with 2.2 mL of lM HCl solution then partitionedbetween 20 mL of ethyl acetate and 20 mL of water. The organic layer wasseparated, washed with 20 mL of brine, dried (magnesium sulfate) andconcentrated in vacuo to give a solid. The crude solid was purified byrecrystallization (ethyl acetate) to afford 230 mg (0.40 mMol, 78%) oftitle acid as a white solid, mp 159°-161°.

IR(KBr): 3432 (broad), 2945, 1719, 1642, 1601, 1521, 1302, 1148 cm⁻¹.

MS(CI): 598 (M+NH₄)⁺.

OR: [α]_(D) =+9.0° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.41, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₁ H₃₆ N₂ O₇ S:

C, 64.21; H, 6.25; N, 4.83; S, 5.52;

Found: C, 64.32; H, 6.19; N, 4.79; S, 5.35

EXAMPLE 78[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]-N-ethylbenzenepropanamide

To a stirred solution of 0.11 g (0.58 mmol) of WSC and 0.08 g (0.58mmol) of HOBT H₂ O in 30 mL of DMF at room temperature under argon wasadded 0.05 g (0.58 mmol) of ethylamine hydrochloride, 0.12 g (1.17 mmol)of triethylamine and 0.30 g (0.58 mmol) of Example 1 compound. Theresulting yellow solution was stirred for 2.5 days. 15 mL of water wasadded, and the mixture was extracted with three 50 mL portions of EtOAc.The organic layers were combined, washed with brine, dried over MgSO₄,and concentrated to obtain a yellow solid. This was crystallized fromchloroform and hexane, and 0.13 g (40%) of a title amide in the form ofa white solid was obtained.

R_(f) =0.4; 50% (0.5% AcOH/EtOAc)/Hexane, m.p. 55°-156° C.

[α]_(D) =+3.6 at c=0.90 g/100 gmL in CH30H at room temperature.

EXAMPLE 79[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanamide

To a stirred solution of 0.11 g (0.58 mmol) of WSC and 0.08 g (0.58mmol) of HOBT H₂ O in 30 mL of DMF at room temperature under argon wasadded 0.032 g (0.58 mmol) of ammonium chloride, 0.12 g (1.17 mmol) oftriethylamine and 0.30 g (0.58 mmol) of Example 1 compound. Theresulting yellow solution was stirred for 2.5 days. 15 mL of water wasadded, and the mixture was extracted with three 50 mL portions of ethylacetate The organic layers were combined, washed with brine, dried overMgSO₄, and concentrated to obtain a yellow solid. This was crystallizedfrom chloroform and hexane, and 0.29 g (100%) of a title amide in theform of a white solid was obtained

R_(f) =0.20, EtOAc (silica gel) m.p. 173°-174° C.

[α]_(D) =+15 at c=0.14 g/100 mL in CH₂ OH at room temperature.

EXAMPLE 80[1S-(1α,2α,3α,4α)]-2-[[3-4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, ethyl ester

To a flask containing 20 mL of dry ethanol (distilled from Mg(OC₂ H₅)2)was added 0.25 mL of acetyl chloride. This solution was stirred for 90minutes at which time 353 mg of Example 1 acid product (0.69 mmol) wasadded. This solution was stirred at 23° C. for 90 minutes at which timeTLC analysis showed the reaction to be essentially complete. Thereaction mixture was diluted with CH₂ Cl₂ and concentrated in vacuo. Theresidue was dissolved in CH₂ Cl₂ and stored in the refrigeratorovernight. The solution was diluted to ca. 40 mL with CH₂ Cl₂ and washedwith 20 mL of saturated aqueous NaHCO₃ solution. The organic layer wasdried over MgSO₄, filtered, and concentrated in vacuo to afford a whitesolid. This was triturated with ether and then diluted with an equalvolume of hexane. The slurry was chilled and the solid was collected toafford 280 mg (76%) of title ester, m.p. 130°-1° C.

Analysis Calc'd for C₃₂ H_(44l) N₂ O₅.0.35 H.sub. O: C, 70.78; H, 8.17;N, 5.16;

Found: C, 70.75; H, 7.85; N, 4.79

TLC: silica gel, 3% CH₃ OH/CH₂ Cl₂, R_(f) =0.65, EtOAc, vanillin.

[α]_(D) =+3.68 (c=1.44, CH₃ OH)

⁻⁻ C NMR(CDCl₃ 67.5 MHz): δ 163.7, 160.5, 140.5, 138.5, 137.8, 136.2,129.7, 128.9, 126.6, 126.4, 79.7, 78.6, 60.4, 50.0, 39.1, 37.5, 37.1,35.1, 33.3, 33.2, 32.5, 29.9, 28.8, 27.6, 26.7, 26.4, 26.4, 24.2, 14.2.

EXAMPLE 81[1S-1α,2α,3α,4α)]-N-4-(Cyclohexylbutyl)-2-2-[[2-(3-hydroxypropyl)]phenyl]methyl]-7-oxabicyclo-2.2.1]hept-3-yl]-4-oxazolecarboxamide

To a slurry of 420 mg of impure Example 80 ester in 20 mL of ether wasadded 56.3 mg of LiBH₄ (2.56 mmol). After the reaction mixture wasstirred for 5 minutes, it appeared that additional solid had formed so5.0 mL of distilled THF was added. The reaction mixture was stirred at23° C for 24 hours and then quenched by the addition of lN HCl₂ solutionuntil the gas evolution ceased and the pH=1. This was then concentratedin vacuo to remove most of the THF, diluted with 20 mL of water, andextracted with 25 mL of ether. The aqueous layer was extracted with two25 mL portions of CH₂ Cl₂. The combined organic layers was dried(MgSO₄), filtered, and concentrated in vacuo. The crude product waschromatographed on 40 g of silica gel using 3% CH₃ OH/CH₂ Cl₂ as eluentto afford 280 mg of impure alcohol. This was then dissolved in 1-2 mL ofCH₂ Cl₂, diluted with ether, warmed and diluted with a near equal volumeof hexane. On standing in the refrigerator, very fine white crystalsformed. These were collected and dried in vacuo to afford 120.5 mg ofpure title alcohol, m.p. 119°-121° C.

Analysis Calc'd for C₃₀ H₄₂ N₂ O₄ : C, 72.84; H, 8.56; N, 5.66;

Found: C, 73.07; H, 8.68; N, 5.61

TLC: silica gel, 3% CH₃ OH/CH₂ Cl₂, R_(f) =0.35, vanillin.

[α]_(D) =+3.97 (c=0.94, CH₃ OH).

¹³ C NMR (CDCl₃, 67.5 MHz): δ 163.9, 160.6, 140.5, 140.3, 137.8, 136.3,129.6, 129.4, 126.5, 126.1, 79.8, 78.6, 62.1, 50.1, 47.0, 39.2, 37.5,37.1, 34.1, 33.4, 32.1, 29.9, 28.8, 26.7, 26.4, 24.2.

EXAMPLE 82[1S-1α,2α,3α,4α)]-2-[[3-[4-[(Phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl-benzenepropanicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of Example 2, Part J acid in 20 mLdry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop of DMF,followed by 310 μL (0.62 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalyl chloridesolution. The reaction was stirred at room temperature until gasevolution ceased (about 30 minutes), then the mixture was concentratedin vacuo to give the crude acid chloride as a pale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 58 mg (0.62 mMol, Aldrich) of aniline in 5 mL CH₂ Cl₂. The reactionwas stirred at 0° for 16 hours, then partitioned between 80 mL ethylacetate/60 mL lM HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica, 1:2 ethylacetate/hexane) to give 180 mg (0.39 mMol, 78%) of title ester as awhite solid, mp 177°-178°.

EXAMPLE 83[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanicacid

To a mixture of 180 mg (0.39 mMol) of Example 82 ester in 8 mL distilledTHF/2 mL water was added 33 mg (0.78 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 4 hours at roomtemperature, then quenched by the addition of 1.6 mL (1.6 mMol) 1M HCl.The mixture was partitioned between 60 mL ethyl acetate/60 mL water. Theethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give 170 mg (0.38 mMol, 98%) of title acid, as a white foam, mp170°-172°.

IR (KBr): 2953, 2931, 2872, 1728, 1622, 1601, 1577 cm⁻¹.

MS(CI): 447 (M+H)⁺.

OR: [α]_(D) =+4° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.43, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₆ H₂₆ N₂ O₅ : C, 69.94; H, 5.87; N, 6.28.

Found: C, 69.70; H, 5.88; N, 6.17

EXAMPLE 84[1S-(1α,2α,3α,4α)]-2-[3-[4-[(Pentylmethylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol, L223-88-23) of Example 2, Part Jacid in 20 mL dry CH₂ Cl₂ (distilled from P 05) was added 1 small dropof DMF, followed by 310 μL (0.62 mMol, 2M/CH₂ Cl_(g2), Aldrich) ofoxalyl chloride solution. The reaction was stirred at room temperatureuntil gas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo to give the crude acid chloride as a pale yellowsolid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 170 μL (1.25 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 86 mg (0.62 mMol) of methyl(5-n-pentyl)amine hydrochloride in 5 mLCH₂ Cl₂ . The reaction was stirred at 0° for 16 hours, then partitionedbetween 80 mL ethyl acetate/60 mL 1M HCl. The ethyl acetate layer wasseparated, dried (MgSO₄) and concentrated in vacuo to give a crudeyellow solid. The crude solid was flash chromatographed (Merck silica,1:2 ethyl acetate/hexane) to give 160 mg (0.34 mMol, 66%) of title esteras a yellow oil.

EXAMPLE 85[1S-(1α,2α,3α,4α)]-2-[[3-4-[(Pentylmethylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 160 mg (0.34 mMol) of Example 84 ester in 8 mL distilledTHF/2 mL water was added 29 mg (0.68 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 4 hours at roomtemperature, then quenched by the addition of 1.4 mL (1.4 mMol) 1M HCl.The mixture was partitioned between 60 mL ethyl acetate/60 mL water. Theethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give 150 mg (0.33 mMol, 97%) of title acid as a yellow oil.

IR (KBr): 2980, 2951, 2941, 1726, 1703, 1672, 1624 cm⁻¹.

MS(CI): 455 (M+H)⁺.

OR: [α]_(D) =+27° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.38, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₆ H₃₄ n₂ O₅ : C, 68.70; H, 7.54; N, 6.16;

Found: C, 69.08; H, 7.82; N, 5.82

EXAMPLE 86[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[Amino[1,1'biphenyl]-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of oxazole acid prepared in Example2, Part J in 2 mL of dry methylene chloride (distilled from phosporouspentoxide) was added at room temperature a small drop of DMF then 55 μL(0.63 mMol, Aldrich) of oxalyl chloride. The solution was stirred untilgas evolution ceased, about 30 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.52 mMol) in 4 mL ofdry methylene chloride cooled in an ice-bath was added 105 mg (0.62mMol, Aldrich) of 4-aminobiphenyl followed by 110 μL (0.78 mMol,distilled from calcium hydride) of triethylamine. The reaction mixturewas warmed to room temperature and stirred for 1 hour. The resultingyellow solution was partitioned between 20 mL 1M aqueous HCl₂ solutionand 20 mL of hot ethyl acetate. The organic layer was separated, dried(magnesium sulfate) and concentrated in vacuo to give a yellow solid.The crude material was recrystallized (ethyl acetate/hexane) to afford212 mg (0.40 mMol, 76%) of title ester as a white solid, mp 174°-175°.

EXAMPLE 871S-1α,2α,3α,4α)]-[2-[[3-[4-[[Amino[[1,1'biphenyl]-4-yl]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid

A mixture of 160 mg (0.93 mMol) of Example 86 ester and 4 mL of THF waswarmed until homogeneous then 1 mL of water was added followed by 25 mg(0.60 mMol, Aldrich) of lithium hydroxide monohydrate. The reactionmixture was stirred at room temperature for 4 hours then acidified byaddition of 1.2 mL of 1M HCl₂ solution. The resulting solution waspartitioned between 20 mL of 1M aqueous HCl₂ solution and 20 mL of ethylacetate. The organic layer was separated, dried (magnesium sulfate) andthen concentrated in vacuo to give a solid. The crude material wasrecrystallized (acetonitrile) to afford 138 mg (0.26 mMol, 88%) of titleacid as white crystals, mp 204°-206°.

IR(KBr): 3444 (broad), 1688, 1597, 1526, 1489, 1406, 1103 cm⁻¹.

MS(CI): 523 (M+H)⁺.

OR: [α]_(D) =-2° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.47, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₂ H₃₀ N₂ O₅ : C, 73.54; H, 5.79; N, 5.36;

Found: C, 73.41; H, 5.68; N, 5.22

EXAMPLE 88[1S-(1α,2α,3α,4α)]-2-3-[4-[[(4-Cyclohexylbutyl)-methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol, L223-88-23) of acid prepared inExample 2, Part J in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added1 small drop of DMF, followed by 310 μL (0.62 mMol, 2M/CH₂ Cl₂,Aldrich)of oxalyl chloride solution. The reaction was stirred at roomtemperature until gas evolution ceased (about 30 minutes), then themixture was concentrated in vacuo to give the crude acid chloride as apale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 170 μL (1.25 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 160 mg (80% pure, 128 mg, 0.62 mMol) of 4-cyclohexylbutyl(methyl)amine hydrochloride in 5 mL CH₂ Cl₂. The reaction was stirred at 0° for16 hours, then partitioned between 80 mL ethyl acetate/60 mL lM HCl. Theethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give a crude yellow solid. The crude solid was flashchromatographed (Merck siilca, 1:2 ethyl acetate/hexane) to give 200 mg(0.37 mMol, 72%) of title ester as a white solid.

EXAMPLE 89[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)-methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1hept-2-yl]methyl]benzenepropanoicacid

To a mixture of 130 mg (0.25 mMol) of Example 88 ester in 8 mL distilledTHF/2 mL water was added 20 mg (0.48 mMol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 4 hours at roomtemperature, then quenched by the addition of 1.0 mL (1.0 mMol) 1M HCl.The mixture was partitioned between 80 mL ethyl acetate/80 mL water. Theethyl acetate layer was separated and the water layer was extracted with2×50 mL of ethyl acetate. The combined ethyl acetate layers were dried(MgSO₄) and concentrated in vacuo to give 100 mg (0.19 mMol, 79%) oftitle acid as a white foam, mp 60°-65°.

IR (KBr): 3439, 3431, 2922, 2850, 1716, 1697, 1612, 1585 cm⁻¹.

MS(CI): 523 (M+H)⁺.

OR: [α]_(D) =+20° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.31, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₁ H₄₂ N₂ O₅ +0.25 mol H₂ O:

C, 70.61; H, 8.13, N, 5.31

Found: C, 70.52; H, 8.12, N, 5.04

EXAMPLE 90[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Phenylbutyl)amino]-carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]-methvl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of acid prepared in Example 2, PartJ in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (0.62 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalylchloride solution. The reaction was stirred at room temperature untilgas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo to give the crude acid chloride as a pale yellowsolid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 93 mg (0.62 mMol, Aldrich) of 4-phenylbutylamine in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate/60 mL 1M HCl. The ethyl acetate layer was separated, dried(MgSO₄) and concentrated in vacuo to give a crude yellow solid. Thecrude solid was flash chromatographed (Merck silica, 1:2 ethylacetate/hexane) to give 250 mg (0.48 mMol, 93%) of title ester as awhite solid, mp 132°-134°.

EXAMPLE 91[1S-(1α,2α,3α,4α)]-2-[3-[4-[(4-Phenylbutyl)amino]-carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid

To a solution of 237 mg (0.46 mMol) of Example 90 ester in 8 mLdistilled THF/2 mL water was added 39 mg (0.92 mMol, Aldrich) of lithiumhydroxide monohydrate. The reaction was stirred vigorously for 4 hoursat room temperature, then quenched by the addition of 1.9 mL (1.9 mMol)1M HCl. The mixture was partitioned between 60 mL ethyl acetate/60 mLwater. The ethyl acetate layer was separated, dried (MgSO₄) andconcentrated in vacuo to give crude yellow foam. The crude foam wasflash chromatographed (Merck silica, ethyl acetate then 1:9methanol:methylene chloride) to give 170 mg (0.34 mMol, 74%) of titleacid as a white solid, mp 148°-150°.

IR (KBr): 3423, 2935, 1716, 1653, 1602, 1523 cm⁻¹.

MS(CI): 503 (M+H)⁺.

OR: [α]_(D) =+7° (c=1.0 in chloroform). TLC: R_(f) (silica gel, 1:9methanol/methylene chloride)=0.51, ammonium molybdate/ceric sulfate andUV, homogeneous.

Analysis Calc'd for C₃₀ H₃₄ N₂ O₅ +0.4 mol H₂ O: C, 70.69; H, 6.88; N,5.50;

Found: C, 70.95; H, 6.79; N, 5.17

EXAMPLE 921S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(Phenylmethoxy)-phenyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 500 mg (1.30 mMol) of oxazole acid prepared in Example2, Part J in 5 mL of dry methylene chloride (distilled from phosphorouspentoxide) was added at room temperature a small drop of DMF then 135 μL(1.54 mMol, Aldrich) of oxalyl chloride. The solution was stirred untilgas evolution ceased, about 30 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 1.30 mMol) in 6 mL ofdry methylene chloride cooled in an ice-bath was added 400 μL (1.85mMol, distilled from calcium hydride) of triethylamine followed by 368mg (1.56 mMol, Aldrich) of 4-benzyloxyaniline hydrochloride. Thereaction mixture was stirred at 0° for 10 minutes then at roomtemperature for 1 hour. The resulting yellow solution was partitionedbetween 20 mL lM aqueous HCl₂ solution and 20 mL of ethyl acetate. Theorganic layer was separated, dried (magnesium sulfate) and concentratedin vacuo to give a yellow solid. The crude material was recrystallized(ethyl acetate/hexane) to afford 560 mg (0.99 mMol, 76%) of title esteras a white solid, mp 154°-155°.

EXAMPLE 93[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(Phenylmethoxy)-phenylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A solution of 515 mg (0.92 mMol) of Example 92 ester and 78 mg (1.9mMol, Aldrich) of lithium hydroxide monohydrate in 9 mL of 2:1 THF/waterwas stirred at room temperature for 4 hours. The resulting solution waspartitioned between 20 mL of 1M aqueous HCl₂ solution and 20 mL of ethylacetate. The organic layer was separated, dried (magnesium sulfate) andthen concentrated in vacuo to give a solid. The crude material wasrecrystallized (ethyl acetate/hexane) to afford 380 mg (0.69 mMol, 75%)of title acid as white crystals, mp 192°-193°.

IR(KBr): 3434 (broad), 1711, 1682, 1640, 1603, 1510, 1229 cm⁻¹.

MS(CI): 553 (M+H)⁺.

OR: [α]_(D) =+4.4° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.53, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₃ H₃₂ N₂ O₆ : C, 71.72; H, 5.84; N, 5.07;

Found: C, 71.68; H, 5.74; N, 4.95.

EXAMPLE 94[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Hydroxyphenyl)amino]-carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A mixture of 200 mg (0.36 mMol) of Example 93 acid and 40 mg of 20%palladium hydroxide on carbon catalyst (Aldrich) in 20 mL of sieve-driedmethanol was stirred rapidly under an atmosphere of hydrogen (balloon)at room temperature for 2 hours. The reaction mixture was passed througha 4 μM polycarbonate membrane then the filtrate was concentrated invacuo to give a foam. The foam was crystallized (ethyl acetate/hexane)to afford 142 mg (0.31 mMol, 86%) of title acid as small white orystals,mp 185°-186°.

IR(KBr): 3426, 1713, 1636, 1514, 1435, 1215 cm⁻¹.

MS(CI): 463 (M+H)⁺.

OR: [α]_(D) =-17° (c=0.5 in methanol).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.31, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₆ N₂ O₆ : C, 67.52; H, 5.67; N, 6.06;

Found: C, 67.35; H, 5.51; N, 5.74.

EXAMPLE 95[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]-N-methylsulfonylbenzenepropanamide

Into an over-dried flask under argon was placed 0.25 g Example 1 acid(0.49 mmol), 0.07 g N,N-dimethylaminopyridine (0.6 mmol), 0.13 gmethanesulfonamide (1.4 mmol), and 0.13 g WSC (0.7 mmol). To this wasadded by syringe 2 mL of DMF (Burdick & Jackson, new bottle, assayed0.010% water). Upon stirring at room temperature, all of the solidcomponents dissolved. TLC indicated nearly complete reaction after 2.5hours. After 1 day (TLC showed starting material consumed), the reactionmixture was diluted with EtOAc, washed with 1.0M aqueous HCl₂ threetimes, dried over Na₂ SO₄, and evaporated. The residue was flashchromatographed (35% to 50% [5% AcOH in EtOAc] in hexane gradient) toobtain, after azeotroping away AcOH with toluene and crystallizing byaddition and evaporation of Et₂ O, 0.26 g of pure title amide, a whitesolid (mp 154°-156°). The yield of product was 91%.

[α]° D=+20.1° in CHCl₃ at c=1.71 g/100 mL.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                               Example 1 acid                                                                          0.36                                                                Title amide                                                                             0.33                                                         ______________________________________                                    

EXAMPLE 96[1S-[1α,2α,3α(E),4α]]-2-[[3-[4-[[(2-Propynyl]-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirring mixture of 137 mg (C₂ H₅)₃ N (1.36 mmol, 1.6 equiv) and 92mg propargylamine hydrochloride (1.00 mmol, 1.2 equiv) in 6 mL CHCl₃under argon at room temperature, was added 340 mg of Example 2, Part Jacid chloride (0.84 mmol) in 6 mL CHCl₃. After stirring overnight, TLCindicated incomplete reaction. Therefore, 109 mg (C₂ H₅)₃ N (1.08 mmol,1.3 equiv) and 92 mg propargylamine hydrochloride (1.00 mmol, 1.2 equiv)were added. TLC indicated complete reaction after 5 minutes. Thereaction mixture was evaporated and flash chromatographed (silica, 50%EtOAc in hexane) to obtain 350 mg of pure title amide as a white solid.The yield of product was quantitative.

    ______________________________________                                        TLC (1% F.sub.3 CCO.sub.2 H, 1% CH.sub.3 OH, 98% EtOAc -                      ______________________________________                                        anisaldehyde):                                                                Acid of Example 2 Part J                                                                          0.86                                                      title ester         0.76                                                      ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 6 173.0, 163.9, 160.1, 140.8, 138.4,137.7, 135.5, 129.6, 128.9, 126.5, 126.5, 79.6, 79.2, 78.5, 71.4, 51.5,49.9, 46.8, 34.8, 32.3, 29.8, 28.7, 28.5, 27.5.

EXAMPLE 97[1S-[1α,2α,3α(E),4o]]-2-[[3-[4-[[(2-Propynyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid

To 350 mg of pure Example 96 amide in 10 mL CH₃ OH at room temperature,was added 10 mL of 1.0M aqueous NaOH solution and 10 mL THF. Afterstirring the mixture for 2 hours, 14 mL of 1M aqueous HCl solution wasadded to lower the pH to 1. Extraction with CH₂ Cl₂ followed. Theextracts were dried over Na₂ SO₄, and solvent evaporation gave 360 mg oftitle acid as a white solid in quantitative yield.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                        Example 98 amide 0.30                                                         title acid       0.17                                                         ______________________________________                                    

EXAMPLE 98[1S-[1α,2α,3α(E),4α]]-2-[[3-[4-[[(3-Iodo-2-propenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A.[1S-[1α,2α,3α(E),4α]]-2-[[3-4-[[(3-Tributylstannane-2-propenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid

Under argon a mixture of 120.9 mg (0.296 mmol)of Example 97 acid, 6.3 mgazobisisobutyronitrile (AIBN) (0.038 mmol, 0.13 equiv), and 332 mg (C₄H₉)₃ SnH (1.14 mmol, 3.8 equiv) in 0.4 mL freshly distilled THF washeated to reflux for 10 minutes. The reaction solution was evaporatedand directly flash chromatographed (silica, 25% to 47%[5% AcOH in EtOAc]in hexane gradient). Evaporation of the chromatography solvent wasquickly followed by coevaporation with toluene to remove residual AcOH.After exposure to high vacuum, 130 mg of nearly pure title vinylstannane, an oil, was obtained. Title vinyl stannane was contaminatedwith a trace of the unsubstituted allyl analogue. The yield of titlecompound was 63%.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                        Example 99 acid  0.20                                                         title vinylstannane                                                                            0.45                                                         ______________________________________                                    

⁻⁻ C NMR(67.8 MHz in CDCl₃) δ 176.8, 163.9, 160.6, 142.9, 141.2, 138.5,137.7, 135.8, 130.7, 129.7, 129.0, 126.6, 126.6, 79.7, 78.6, 49.9, 46.9,44.5, 34.8, 32.5, 29.8, 29.0, 28.8, 27.4, 27.2, 13.6, 9.4.

B.[1S-[1α,2α,3α(E),4α]]-2-[[3-[4-[[(3-Iodo-2-propenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid

This chemistry is described in J.L. Musachio and J.R. Lever, TetrahedronLetters, 1989, 30, 3613.

To a solution of 121 mg Part A compound (0.17 mmol) in 34 mL CH₃ OH, 10mL pH 7.7 buffer (preparation: 2.72 g KH₂ PO₄ (20 mmol) and 20.9 g K₂HPO₄ (120 mmol) dissolved to 1.0L with Millipore purified water), and 10mL water stirring at room temperature, was added 52 mg NaI (0.41 mmol),then 47 mg Chloramine-T hydrate (<0.21 mmol). The solids dissolved, andan iodine color formed. After 1 hour (solution still colored), 2 mL 3Maqueous NaHSO₃ and 2 mL 1M aqueous HCl₂ were added. The mixture wasextracted three times with CH₂ Cl₂, and the extracts were dried over Naand evaporated. Flash chromatography (silica gel, 30% to 40% [5% AcOH inEtOAc] in hexane gradient), collecting only the pure fractions, gave 41mg (45% yield) of title compound, a white solid (mp 142°-145°).

[α]°_(D) =+11.1° in CHCl₂ at c=1.29 g/100 mL.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                        Part A compound  0.59                                                         Example 96 ester 0.39                                                         ______________________________________                                    

EXAMPLE 99

[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Hydroxy-3-iodophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxa-bicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a solution of 209 mg Example 37 acid (0.40 mmol) in 8 mL CH₃ OH and 8mL pH 7.7 buffer (preparation: 2.72 g KH₂ PO₄ (20 mmol) and 20.9 g K₂HPO₄ (120 mmol) dissolved to 1.0 L with Millipore purified water)stirring at room temperature, was added 79 mg NaI (0.53 mmol), then 128mg Chloramine-T hydrate (<0.56 mmol). The solids dissolved, an iodinecolor formed, and the mixture then decolorized. After 1 hour, 2 mL 3Maqueous NaHSO₃ and 2 mL 1M aqueous HCl were added. The mixture wasextracted three times with CH₂ Cl₂, and the extracts were dried over Na₂SO₄ and evaporated. Flash chromatography (silica gel, 30% to 50% [5%AcOH in EtOAc] in hexane gradient) separated about 125 mg of impureundesired diiodo product from the desired product and remaining startingmaterial. The latter two were separated by flash chromatography using adifferent solvent system (10% to 15% (10% AcOH in acetone] in toluenegradient). This gave 53 mg (21% yield) of pure title compound, whichsolidified upon addition and evaporation of Et₂ O (mp 84°-91°).

[α]°_(D) =+11.7° in CHCl₃ at c=0.76 g/100 mL.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                        Example 37 acid  0.20                                                         title compound   0.24                                                         diiodo product   0.36                                                         ______________________________________                                    

    ______________________________________                                        TLC (5% AcOH in [20% acetone in toluene]                                      anisaldehyde):                                                                ______________________________________                                        Example 37 acid  0.32                                                         title compound   0.38                                                         diiodo product   0.46                                                         ______________________________________                                    

EXAMPLE 100[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, monopotassium salt

To a slurry of 262 mg Example 1 acid (0.516 mmol) in 10 mL CH₃ OHstirring at room temperature, was added 473 μL of 1.09M aqueous KOHsolution (0.516 mmol). (The KOH solution was prepared by dissolving in50.0 mL of house line purified water 3.51 g of 86.8% pure KOH, newbottle, Mallinckrodt, 3.05 g net, 54.3 mmol). The starting materialslowly dissolved. The resulting solution was evaporated to a glass on arotoevaporator. Addition and evaporation of CH₃ CN caused the glass tosolidify. After addition of more CH₃ CN, the solid was filtered, washingwith CH₃ CN, and exposed to high vacuum. This gave 224 mg (80% yield) oftitle salt (mp 90°-110°).

[α]°_(D) =+0.2° in CH₃ OH at c=1.41 g/100 mL.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                               Example 1 acid                                                                          0.36                                                                title salt                                                                              0.36                                                         ______________________________________                                    

EXAMPLE 101[S-(1α,2α,3α,4α)]-2-[3-[4-Cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept--yl]methyl]benzenepropanoicacid, monosodium salt

To a slurry of 324 mg of Example 1 acid (0.638 mmol) in 20 mL CH₃ OHstirring at room temperature, was added 638 μL of 1.00M aqueous NaOHsolution (Mallinckrodt). The starting material slowly dissolved. Theresulting solution was evaporated to a glass on a rotoevaporator.Addition and evaporation of CH₂ CN caused the glass to solidify. Afteraddition of more CH₂ CN, the solid was filtered and dried under highvacuum. This gave 290 mg (86% yield) of title salt (mp 274°-275°).

[α]°_(D) =-0.3° in CH₃ OH at c=1.50 g/100 mL.

    ______________________________________                                        TLC (50% [5% AcOH in EtOAc] in hexane -                                       anisaldehyde):                                                                ______________________________________                                               Example 1 acid                                                                          0.36                                                                title salt                                                                              0.36                                                         ______________________________________                                    

EXAMPLE 102[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-Methoxyphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of acid prepared as described inExample 2, Part J in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added1 small drop of DMF, followed by 310 μL (0.62 mMol, 2M/CH₂ Cl₂, Aldrich)of oxalyl chloride solution. The reaction was stirred at roomtemperature until gas evolution ceased (about 30 minutes), then thereaction mixture was concentrated in vacuo to give the crude acidchloride as a pale yellow solid.

To a solution of the crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 77 mg (0.62 mMol, Aldrich) of p-anisidine in 5 mL CH₂ Cl₂ . Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate and 80 mL 1M HCl. The ethyl acetate layer was separated,dried (MgSO₄) and concentrated in vacuo to give a yellow solid. Thecrude solid was flash chromatographed (Merck silica, 1:2 ethylacetate/hexane) then recrystallized (hexane/ethyl acetate) to give 210mg (0.43 mMol, 82%) of title ester as a white solid, mp 153°-155°.

EXAMPLE 103[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-Methoxyphenyl)aminocarbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoic acid

To a solution of 210 mg (0.43 mMol) of Example 102 ester in 8 mLdistilled THF and 2 mL water was added 36 mg (0.86 mMol, Aldrich) oflithium hydroxide monohydrate. The reaction was stirred vigorously for 4hours at room temperature, quenched by the addition of 1.7 mL (1.7 mMol)1M HCl₂ then partitioned between 60 mL ethyl acetate and 60 mL water.The ethyl acetate layer was separated, dried (MgSO₄) and concentrated invacuo to give 200 mg (0.42 mMol, 98%) of title acid, as a solid whitefoam.

IR (KBr): 3437, 3144, 2987, 1710, 1637, 1604, 1525 cm⁻¹.

MS(CI): 477 (M+H)⁺.

OR: [α]_(D) =+0° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.54, ammonirmmolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₇ H₂₈ N₂ O₆ +0.39 H₂ O: C, 67.06; H, 6.00; N,5.79;

Found: C, 67.46; H, 6.02; N, 5.39

EXAMPLE 104[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Chlorophenyl)amino]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mMol) of acid prepared in Example 2, PartJ in 20 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (0.62 mMol, 2M/CH₂ Cl₂, Aldrich) of oxalylchloride solution. The reaction was stirred at room temperature untilgas evolution ceased (about 30 minutes), then the reaction mixture wasconcentrated in vacuo to give the crude acid chloride as a pale yellowsolid.

To a solution of the crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 120 μL (0.83 mMol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of a solutionof 79 mg (0.62 mMol, Aldrich) of p-chloroaniline in 5 mL CH₂ Cl₂. Thereaction was stirred at 0° for 16 hours, then partitioned between 80 mLethyl acetate and 80 mL 1M HCl. The ethyl acetate layer was separated,dried (MgSO₄) and concentrated in vacuo to give a crude yellow solid.The crude solid was flash chromatographed (Merck silica, 1:4 ethylacetate/ hexane) to give a yellow solid. The crude solid wasrecrystallized (hexane/ethyl acetate) to give 170 mg (0.34 mMol, 66%) oftitle ester as a white solid, mp 179°-181°.

EXAMPLE 105 [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Chlorophenyl)amino]-carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

To a solution of 170 mg (0.34 mMol) of Example 104 ester in 8 mLdistilled THF/2 mL water was added 29 mg (0.92 ;mMol, Aldrich) oflithium hydroxide monohydrate. The reaction was stirred vigorously for 4hours at room temperature, then quenched by the addition of 1.4 mL (1.4mMol) 1M HCl₂ and partitioned between 60 mL ethyl acetate and 60 mLwater. The ethyl acetate layer was separated, dried (MgSO₄) andconcentrated in vacuo to give 160 mg (0.33 mMol, 98%) of title acid as awhite solid, mp 220°-221°.

IR (KBr): 3435, 3107, 1709, 1687, 1597, 1581 cm⁻¹.

MS(CI): 498 (M+NH₄)⁺.

OR:[α]_(D) =-3° (c=1.0 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.56, ammonirmmolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₆ H₂₅ N₂ O₅ Cl:

C, 64.93; H, 5.24; N, 5.83; Cl, 7.37;

Found: C, 64.83; H, 5.19; N, 5.56; Cl, 7.32

EXAMPLE 106[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[3-(1H-Imidazol-1yl)propyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 0.21 g (0.52 mmol) Example 2, Part J acid chloride in 5mL of chloroform, was added 0.071 g (0.58 mmol) of1-(3-aminopropyl)-imidazole and 0.07 g (0.7 mmol) triethylamine. Themixture was stirred at room temperature for 20 hours then concentratedon a rotoevaporator. The residue was diluted with 50 mL EtOAc and 10 mLwater. The organic layer was separated, and the aqueous layer wasextracted with 20 mL of EtOAc twice. The organic layers were combined,washed with brine, dried over MgSO , and concentrated to obtain 0.25 g(98%) of an oil.

R_(f) =0.6 in 10% CH₃ OH in CH₂ Cl₂, UV, Ce(SO₄)₂.

⁻⁻ C NMR (67.8 MHz, CDCl₃): δ 173.2, 163.9, 161.0, 140.7, 138.4, 138.0,137.7, 136.0, 135.8, 129.6, 128.9, 127.0, 126.7, 126.5, 79.8, 78.7,51.6, 49.9, 46.9, 46.9, 36.1, 34.9, 32.4, 31.3, 29.8, 28.9, 27.6.

EXAMPLE 107[1S-1α,2α,3α,4α)]-2-[[3-[4-[[[3-(1H-Imidazol-1yl)propyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A solution of 0.25 g (0.51 mmol) of Example 106 ester in 1 mL of 1NNaOH, 2 mL of methanol, and 2 mL of THF was stirred for 2.5 days. Thereaction mixture was washed with 20 mL of EtOAc (3 times) to removeunreacted ester. The aqueous layer was acidified with 10% aqueous HCl₂to pH 1 and extracted with CHCl₃ (3 times, 50 mL). The organic layerswere combined, washed with brine, dried over MgSO₄, and concentrated invacuo.. Flash chromatography (silica, 30% PAW [20 parts pyridine:6 partsAcOH:11 parts water]in EtOAc) was followed by coevaporation with CH₃ OHand toluene to remove residual pyridine and AcOH. Any silica gel wasremoved by filtration through a Millipore/ Fluropore membrane filter(0.5 μm FH) with a prefilter pad as a solution in 15% CH₃ OH in EtOAc.The solvent was evaporated, the residue was dissolved in hot water, andthe water was evaporated to produce title compound in the form of a drywhite solid (mp 215°-216° ).

R_(f) =0.16 in 30% PAW [20 parts pyridine:6 parts AcOH: 11 parts water]in EtOAc, anisaldehyde. ROTATION.

EXAMPLE 108[1S-(1α,2α,3α,4α)]-2-3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

A. 3-Amino-2-[[(1,1-dimethylethoxy)- carbonyl]amino]propanoic acid,benzyl ester

To a stirred mixture of [bis(trifluoroacetoxy)iodosylbenzene (2.00 g,4.66 mmol) in 24 mL of 1:1 DMF-water was added N-α-Boc-asparagine benzylester (1.00 g, 3.11 mmol, preparation was described by Wang, G. et al,in J. Org. Chem., Vol, 42, p 1286-1290, 1977). This mixture was stirredin a cold water bath for 15 minutes at which time dry pyridine (0.50 mL,6.21 mmol) was added. The mixture was stirred at room temperature for.4hours and concentrated in vacuo. The crude product was partitionedbetween 10 mL of lN HCl₂ solution and ether (4×15 mL). The aqueous layerwas neutralized with NaHCO₃, saturated with NaCl₂ and extracted withEtOAc (4×15 mL). The combined EtOAc extracts were dried (MgSO₄),filtered and concentrated in vacuo to give 0.53 g (58%) of title amine.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂,R_(f) 0.44, Ce(SO₄)₂.

B.[1S-[1α,2α,3α,4α]]-2-[[3-[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-oxo-3-(phenylmethoxypropyl]amino]oxomethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl-benzenepropanoicacid, methyl ester

To a stirred mixture of Example 2, Part E acid (3.75 g, 11.8 mmol),1-hydroxybenzotriazole monohydrate (1.97 g, 11.8 mmol) and Part A amine(3.30 g, 11.8 mmol) in 80 mL of dry DMF under argon at 0° C. was addedsequentially (C₂ H₅)₃ N (3.28 mL, 23.6 mmol) andethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride salt (2.26 g,11.8 mmol). The mixture was stirred at room temperature for 12 hours andconcentrated in vacuo. The crude product was diluted with 400 mL ofEtOAc and washed with 0.1N NaOH solution (3×40 mL), lN HCl solution(2×40 mL), saturated NaHCO₃ solution (1×40 mL) and brine (1×80 mL). TheEtOAc layer was dried (MgSO₄), filtered and concentrated in vacuo. Thiswas chromatographed on Merck silica gel 60 using 2% CH₃ OH/CH₂ Cl₂ aseluant to give 1.87 g (27%) of title amide.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.76, Ce(SO₄)₂

C.[1S-[1α,2α,3α,4α]]-2-[[3-[[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-oxo-3-(phenylmethoxy)propyl]amino]thioxomethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred mixture of Part B amide (650 mg, 1.12 mmol) in 14 mLbenzene under argon was added Lawesson's reagent (2.93 g, 0.72 mmol).The mixture was heated at 65° C. under argon for 2 hours and cooled toroom temperature. The mixture was diluted with 200 mL of ether andwashed with saturated NaHCO₃ solution (1×30 mL) and brine (1×40 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 24 g of Mercksilica gel 60 using 1:1 ether-hexane as eluant to give 350 mg (52%) oftitle thioamide.

TLC: silica gel, 3:1 ether-hexane, R 0.58, Ce(SOhd 4)₂.

D.[1S-[1α,2α,3α,4αa]]-2-[[3-[1-[(1,1-Dimethylethoxy)carbonyl]-4,5-dihydro-5-[(phenylmethoxy)carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a stirred mixture of Part E thioamide (340 mg, 0.57 mmol), )3P (448mg, 1.71 mmol) and (C₂ H₅)₃ N {0.24 mL, 1.71 mmol) in 6 mL ofacetonitrile was added CCl₂ (0.62 mL, 6.27 mmol). The mixture wasstirred at room temperature for 4 hours and diluted with 100 mL of etherand 10 mL of water. The resulting mixture was saturated with NaCl₂ andextracted with ether (4×40 mL). The combined ether extracts were dried(MgSO₄), filtered and concentrated in vacuo. This was chromatographed on20 g of Merck silica gel 60 using 200 mL of each of 2:1, 1:1, and 1:3hexane-ether as eluant to give 180 mg (56%) of title Boc (orBOC)-imidazoline.

TLC: silica gel, ether, R_(f) 0.24, Ce(SO₄)₂.

E.[1S-[1α,2α,3α,4α]]-2-[[3-[5-[[(4-Cyclohexylbutyl)amino]-carbonyl]-[1-(1,1-dimethylethoxy)carbonyl]-4,5-dihydro-1H-imidazol-2-yl]-7-oxabicyclo[-2.2.1]hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a stirred mixture of Part D Boc-imidazoline (180 mg, 0.32 mmol) in 10mL of methanol under argon was added 20% Pd/,C (36 mg, 20% based on theweight of Part D compound). The atmosphere was replaced with hydrogen byseveral vacuum-fill cycles. The mixture was stirred at room temperaturefor 4.5 hours and the catalyst was filtered off through a 4 μmpolycarbonate film. The catalyst was rinsed with DMF (4×20 mL). Thefiltrate was concentrated in vacuo to give crude acid[1S-[1α,2α,3α,4α]]-2-[3[-5-carboxy-1-[(1,1-dimethylethoxy)carbonyl]-4,5-dihydro-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2yl]-7-oxabicyclo[2.2.1]hept-2-methyl]benzenepropanoicacid, methyl ester. To a stirred mixture of this acid,1-hydroxybenzotriazole monohydrate (54 mg, 0.32 mmol) and4-cyclohexylbutyl amine hydrochloride salt (74 mg, 0.38 mmol) in 3 mL ofDMF under argon at 0° C. was added sequentially (C₂ H₅)₃ N (0.11 mL,0.79 mmol) and ethyl-3-(3dimethylamino)propyl carbodiimide hydrochloridesalt (61 mg, 0.32 mmol). The mixture was stirred at room temperature for18 hours and concentrated in vacuo. The crude product was partitionedbetween 150 mL of EtOAc and 0.lN NaOH solution (2×25 mL), 1N HClsolution (2×25 mL) and saturated NaHCO solution (1×25 mL). The orgar:iclayer was dried (MgSO₄), filtered and concentrated in vacuo. This waschromatographed on 10 g of Merck silica gel 60 using 2% CH₃ OH/CH₂ Cl₂as eluant to give 42.1 mg (22%) of title amide.

TLC: silica gel, 6% CH₂ OH/CH₂ Cl₂, R_(f) 0.58, Ce(SO₄)₂.

F.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclo-hexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclc[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a stirred mixture of Part E amide (555 mg, 0.94 mmol) in 3 mL of dryCH₂ Cl₂ at 0° C. was added 6 mL of trifluoroacetic acid (TFA). Themixture was stirred at room temperature for 3 hours. The mixture wasdiluted with 40 mL of toluene and concentrated in vacuo to give[1S[1α,2α,3α,4α]]-2-[[3-[5-[[(4-cyclohexylbutyl)amino]carbonyl-4,5-dihydro-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester. The crude imidazole-TFA salt was diluted with 150 mLof EtOAc and washed once with 40 mL of saturated NaHCO₃ solution. Theaqueous layer was extracted with EtOAc (1×100 mL). The combined EtOAcextracts were dried (MgSO₄), filtered and concentrated in vacuo. To thiscrude imidazoline in 15 mL of CHCl₃ was added MnO₂ (570 mg, 6.55 mmol).The mixture was stirred at room temperature for 64 hours at which timeMnO₂ (570 mg, 6.55 mmol) was added. The mixture was stirred at roomtemperature for 1 day and another amount of MnO₂ (290 mg, 3.28 mmol) wasadded. The mixture was stirred at room temperature for one more day andagain MnO₂ (190 mg, 2.18 mmol) was added. The mixture was stirred atroom temperature for 1 day and MnO₂ was filtered off through a pad ofCelite and the pad was rinsed with CHCl₃ (6×30 mL). The filtrate wasconcentrated in vacuo and chromatographed on 40 g of Merck silica gel 60(the silica gel was pretreated with 0.1% Et₃ N in CH₂ Cl₂ and thenwashed with CH₂ Cl₂) using 150 mL of CH₂ Cl₂ and 150 mL of 2% CH₃ OH/CH₂Cl₂ as eluant to give 370 mg (76%) of imidazole.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.66, Ce(SO₄)₂.

EXAMPLE 109[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]-carbonyl-1H-imidazol-2-yl]-7-oxabicyclo[-2.2.1]hept-2-yl]methyl]benzenepropanoicacid, hydrochloride salt

To a stirred mixture of Example 108 imidazole (25 mg, 0.05 mmol) in 1 mLof methanol was added 0.4 mL of 2N KOH solution The mixture was stirredat room temperature for 4 hours and concentrated in vacuo to removemethanol. The residue was diluted with 2 mL of CH₂ Cl₂ and acidified topH 2 by the addition of 1N HCl₂ solution. The aqueous layer wasseparated and extracted with CH₂ Cl₂ (4×4 mL). The combined CH₂ Cl₂extracts were dried (Na₂ SO₄), filtered and concentrated in vacuo. Thecrude product was dissolved in 4 mL of CH₂ Cl₂ and combined with 0.25 mLof 4N HCl₂ in ether. The resulting mixture was concentrated in vacuo andtriturated in hot EtOAc (2 mL). The mixture was cooled to roomtemperature and the solid was collected by filtration to give 12.6 mg(48%) of title hydrochloride salt, 25 m.p. 229°-232° C.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.29, Ce(SO₄)2, UV-active.

EXAMPLE 1101S-(1α,2α,3α,4α)]-2-3-[4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1-hept-2-yl]methyl]benzenepropanoicacid

A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxa-zolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, methyl ester

To a solution of 150 mg (0.39 mmol) of oxazole acid prepared in Example2, Part J in 3 mL of dry methylene chloride (distilled from phosphorouspentoxide) was added at room temperature a small drop of DMF then 45 μL(0.51 mmol, Aldrich) of oxalyl chloride. The solution was stirred untilgas evolution ceased, about 30 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.39 mmol) in 3 mL ofdry methylene chloride cooled in an ice-bath was added 82 μL (0.58 mmol,distilled from calcium hydride) of triethylamine followed by 66 μL (0.47mmol, Aldrich) of 2-(4-chlorophenyl)ethylamine. The reaction mixture wasstirred for 15 minutes then partitioned between 20 mL of 1M aqueous HCl₂sc,lution and 20 mL of ethyl acetate. The organic layer was separated,dried (magnesium sulfate) and concentrated in vacuo to give a solid. Thecrude material was recrystallized (ethyl acetate/hexane) to afford 163mg (0.31 mmol, 80%) of title ester as white needles, mp 188°-189° C.,

B.[1S-(1α,2α,3α,4α)]-2-[[3-4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid

A mixture of 150 mg (0.29 mmol) of Part A ester and 50 mg (1.2 mmol,Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/water wasstirred rapidly at room temperature for 5 hours then acidified byaddition of 2.4 mL of 1M aqueous HCl solution. The resulting solutionwas partitioned between 20 mL of water and 20 mL of ethyl acetate. Theorganic layer was separated, dried (magnesium sulfate) and thenconcentrated in vacuo to give a solid. The crude material wasrecrystallized (ethyl acetate) to afford 134 mg (0.26 mmol, 91%) oftitle compound as white crystals, mp 187°-188° C.

IR(KBr): 3437, 1715, 1642, 1605, 1521, 1493, 1094 cm⁻¹.

MS(CI): 509/511 (M+H)⁺.

OR: [α]_(D) =+51° (c=0.25 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.51, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₈ H₂₉ ClN₂ O₅ :

C, 66.07; H, 5.74; N, 5.50; Cl, 6.97;

Found: C, 66.12; H, 5.76; N, 5.43; Cl, 7.16.

[1S-(1α,2α,3α,4α)-2-[[3-[4-(1,1-Dimethylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid

A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-Dimethylethyl)aminocarbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-ylmethyl]benzene-propanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of oxazole acid prepared in Example2, Part J in 2 mL of dry methylene chloride (distilled from phosphorouspentoxide) was added at room temperature a small drop of DMF then 55 μL(0.63 mmol, Aldrich) of oxalyl chloride. The solution was stirred untilgas evolution ceased, about 30 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.52 mmol) in 4 mL ofdry methylene chloride cooled in an ice-bath was added 110 μL (0.78mmol, distilled from calcium hydride) of triethylamine followed by 65 μL(0.70 mmol, Aldrich) of t-butylamine. The reaction mixture was stirredfor 30 minutes. The resulting solution was partitioned between 20 mL 1Maqueous HCl₂ solution and 20 mL of ethyl acetate. The organic layer wasseparated, dried (magnesium sulfate) and concentrated in vacuo to givean oil. The crude material was purified by flash chromatography (Mercksilica, 12×3.0 cm, 2:1 ethyl acetate/hexane) to afford 210 mg (0.48mmol, 92%) of title ester as a colorless oil.

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-Dimethylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid

A mixture of 202 mg (0.46 mmol) of Part A ester and 39 mg (0.93 mMol,Aldrich) of lithium hydroxide monohydrate in 3 mL of 2:1 THF/water wasstirred rapidly at room temperature for 2 hours then acidified byaddition of 2.0 mL of 1M HCl solution. The resulting solution was addedto 20 mL of 1M aqueous HCl₂ solution then extracted with two-20 mLportions of ethyl acetate. The combined organic layers were dried(magnesium sulfate) and then concentrated in vacuo to give an oil. Thecrude material was crystallized (ethyl acetate/ hexane) to afford 162r:g (0.38 mmol, 83%) of title compound as white crystals, mp 155°-156°.

IR(KBr): 3403, 2967, 1715, 1674, 1599, 1520, 1219 cm⁻¹.

MS(CI): 427 (M+H)⁺.

OR: [α]_(D) =+16° (c=0.5 ir: chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.43, ammonir.mmolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₄ H₃₀ N₂ O₅ :

C, 67.58; H, 7.09; N, 6.57;

Found: C, 67.51; H, 7.01; N, 6.56.

EXAMPLE 112[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-Dimethylpropyl)amino]carbonyl]-2-oxazclyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid

A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-Dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of oxazole acid prepared in Example2, Part J in 2 mL of dry methylene chloride (distilled from phosphorouspentoxide) was added at room temperature a small drop of DMF then 55 μL(0.63 mmol, Aldrich) cf oxalyl chloride. The solution was stirred untilgas evolution ceased, about 30 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.52 mmol) in 3 mL ofdry methylene chloride cooled in an ice-bath was added 110 μL (0.78mmol, distilled from calcium hydride) of triethylamine followed by 81 μL(0.69 mmol, Aldrich) of t-amylamine. The reaction mixture was stirredfor 15 minutes. The resulting solution was added to 15 mL of 1M aqueousHCl₂ solution and extracted with two-15 mL portions of ethyl acetate.The organic layers were combined, dried (magnesium sulfate) andconcentrated in vacuo to give an oil. The crude material was purified byflash chromatography (Merck silica, 10×3.0 cm, 2:1 ethyl acetate/hexane)to afford 201 mg (0.44 mmcl, 85%) of title ester as a colorless oil.

B.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-Dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A mixture of 195 mg (0.43 mmol) of Part A ester and 36 mg (0.86 mMol,Aldrich) of lithium hydroxide monohydrate in 3 mL of 2:1 THF/water wasstirred rapidly at room temperature for 2 hours then acidified byaddition of 2.0 mL of 1M HCL solution. The resulting solution was addedto 15 mL of 1M aqueous HCl₂ solution then extracted with two-15 mLportions of ethyl acetate. The combined organic layers were dried(magnesium sulfate) and then concentrated in vacuo to give a solid. Thecrude material was recrystallized (ethyl acetate/ hexane) to afford 160mg (0.36 mmol, 85%) of title compound (SQ 34,805) as white crystals, mp128°-132° C.

IR(KBr): 3437, 1715, 1655, 1599, 1522, 1202 cm⁻¹.

MS(CI): 441 (M+H)⁺.

OR: [α]_(D) =+27° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.49, ammonirmmolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₅ H₃₂ N₂ O₅ :

C, 68.16; H, 7.32; N, 6.36;

Found: C, 68.10; H, 7.36; N, 6.41.

EXAMPLE 113[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Octadecylamino)carbonyl]-2-oxazolyl]-7-ox:abicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid

A.[1S-(1α,2α,3α(Z),4α)]-2-[3-[4-[(Octa-dec-9-enylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid, methyl ester

To a solution of 100 mg (0.26 mmol) of oxazole acid prepared in Example2, Part J in 3 mL of dry methylene chloride (distilled from phosphorouspentoxide) was added at room temperature a small drop of DMF then 30 μL(0.34 mmol, Aldrich) of oxalyl chloride. The solution was stirred untilgas evolution ceased, about 15 minutes, then concentrated in vacuo togive the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.26 mmol) in 3 mL ofdry methylene chloride cooled in an ice-bath was added 50 μL (0.36 mmol,distilled from calcium hydride) of triethylamine followed by a solutionof 83 mg (0.31 mmol, Fluka, practical grade) of oleylamine in 1 mL ofmethylene chloride. The reaction mixture was stirred for 15 minutes. Theresulting solution was partitioned between 15 mL of 1M aqueous HCl₂solution and 20 mL of ethyl acetate. The aqueous layer was separated andextracted with an additional 10 mL of ethyl acetate. The organic layerswere combined, washed with 15 mL of brine, dr.ied (magnesium sulfate)and concentrated in vacuo to give a solid. The crude material waspurified ty flash chromatography (Merck silica, 1533 1.5 cm, 2:1 ethylacetate/hexane) to afford 146 mg (0.23 mmol, 88%) of title ester as awax. g

B.[1S-(1α,2α,3α(Z),4α)]-2-[[3-[4-[Octa-dec-9-enylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid

A mixture of 142 mg (0.22 mmol) of Part A ester and 20 mg (0.48 mmol,Aldrich) of lithium hydroxide monohydrate in 2.5 mL of 4:1 THF/water wasstirred rapidly at room temperature for 16 hours then acidified byaddition of 2.0 mL of 1M HCl solution. The resulting solution waspartitioned between 15 mL of lM aqueous HCl solution and 15 mL of ethylacetate. The organic layer was separated, washed with 15 mL of brine,dried (magnesium sulfate) and then concentrated in vacuo to give 137 mg(0.22 mmol, 100%) of title acid as a white solid, mp 122°-123° C.

C.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Octa-decylamino)carbonyl]-2-oxazolyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]methyl]benzene-propanoicacid

A mixture of 132 mg (0.21 mmol) of Part B olefin and 25 mg of 10%palladium on activated carbon catalyst (Aldrich) in 6 mL of 2:1 ethylacetate/methanol was stirred under an atmosphere of hydrogen (balloon)for 3 hours. The reaction mixture was then passed through a 0.4 μMpolycarbonate membrane and the filtrate concentrated in vacuo to give asolid. The crude solid was recrystallized (ethyl acetate/hexane) toafford 105 mg (0.17 mmol, 81%) of title compound as a white solid, mp135°-136° C.

IR(KBr): 3413, 2923, 2851, 1708, 1648, 1604, 1516, 1218 cm⁻¹.

MS(CI): 623 (M+H)⁺.

OR: [α]_(D) =+21° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.57, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₈ H₅₈ N₂ O₅ :

C, 73.27; H, 9.39; N, 4.50;

Found: C, 73.08; H, 9.49; N, 4.38.

EXAMPLE 1141S-(1α,2α,3α,4α)]-2-[[3-[4-[[[5-(Cyclohexylamino)-5-oxopentyl]amino]carbonyl]-2-oxazolyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A. 5-[[(1,1-Dimethylethoxy)carbonyl]amino]-pentanoic acid

Ihe title compound was prepared employing the procedure described by R.Houssin, J.-L. Bernier, and J.-P. Henichart, Synth., 1988, 259.

B. N-Cyclohexyl-5-[[(1,1-dimethylethoxy)-carbonyl]amino]pentanamide

To a solution of 2.74 g (12.6 mmol) of Part A acid in 50 mL of THF at 0°under argon, was added 2.66 g (16.3 mmol) of carbonyldiimidazole. Thereaction mixture was stirred for 30 minutes and then warmed to roomtemperature for 10 minutes. After recooling to 0°, 1.88 mL (1.63 g, 16.4mmol) of cyclohexylamine and 2.29 mL (1.66 g, 16.4 mmol) oftriethylamine were added. After warming to room temperature, stirringwas continued for 2 days. 10 mL of water was added, and the mixture wasextracted three times with ethyl acetate (10 mL). The organic layerswere combined and dried over MgSO₄, filtered, and concentrated on arotoevaporator to obtain a white solid. This was chromatographed elutingfirst with 70-30 EtOAc-hexane, then EtOAc, to obtain 1.41 g (37%) of apure title product. R_(f) is 0.8 in EtOAc (UV, Ce(SO ₄)₂)

¹³ C NMR (68.7 MHz, CDCl₃) δ 171.7, 156.0, 79.0, 48.0, 39.8, 36.1, 33.1,29.4, 28.3, 25.5, 24.8, 22.7.

C. 5-Amino-N-cyclohexylpentanamide, monohydrochloride

To a solution of 0.50 g (1.67 mmol) of Part B compound in 3 mL CH2C12 at0° under argon, was added 0.26 mL of trifluoroacetic acid (TFA). Afterstirring for 2 hours, the reaction mixture was concentrated on arotoevaporator. The residue was twice coevaporated with 5 mL CHCl₃ toremove excess TFA. The residue was treated with 1 mL of CH₃ OH and 0.18mL concentrated aqueous HCl and concentrated on a rotoevaporater. Theresidue was crystallized from ether to obtain 0.10 g (26%) of a solid astitle product. R_(f) is 0.17 in EtOAc. (UV, Ce(SO₄)₂).

¹³ C NMR (67.8 MHz, CDCl₃): δ 172.9, 38.5, 34.0, 31.7, 25.9, 24.7, 24.4,24.2, 21.9.

D. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[[5-(Cyclohexylamino)-5-oxopentyl]amino]-carbonyl]-₂-oxazolyl]-7-oxabicyclo-[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid,methyl ester

To a solution of 0.10 g (0.42 mmol) of Part C amine in 5 mL ofchloroform at 0° C. under argon, was added 0.14 mL (0.10 g, 1.0 mmol) oftriethylamine and 0.51 mmol of acid chloride prepared in Example 2, PartJ. The mixture was refluxed for 6 hours and stirred at room temperaturefor 15 hours, then diluted with EtOAc and water. The organic layer wasseparated, and the aqueous layer was extracted with 20 mL of EtOActwice. The organic layers were combined, washed with brine, dried overMgSO₄, and concentrated. Flash chromatography (0% to 100% EtOAc inhexane gradient, then 5% CH₃ OH in EtOAc) gave 0.17 g of title productas a clear oil in 59% yield. R_(f) is 0.5 in EtOAc (UV, Ce(SO₄)₂).

¹³ C NMR (67.8 MHz, CDCl₃): δ 173.0, 171.7, 163.8, 160.6, 140.4, 138.4,137.7, 135.7, 129.6, 128.8, 126.5, 126.4, 79.6, 78.5, 51.5, 49.9, 47.9,46.8, 38.1, 36.0, 34.8, 33.0, 32.3, 29.8, 29.0, 28.8, 27.5, 25.5, 24.7,22.9.

E. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[[5-(Cyclo-hexylamino)-5-oxopentyl]amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-methyl]benzenepropanoic acid

A solution of 0.17 g (0.30 mmol) of Part D ester in 1 mL of lN NaOH, 2mL of methanol, 2 mL of THF, and 1 mL water was stirred for 18 hours,then acidified to pH 1.5 with 10% HCl. This was extracted three timeswith 50 mL chloroform. The organic layers were combined, washed withbrine, dried over MgSO₄, and concentrated in vacuo. A clear oil wasobtained. This was crystallized from chloroform and hexane to obtaintitle compound in the form of a white solid (0.11 g, 69%). R_(f) =0.21in 0.5% acetic acid in ethyl acetate (UV, Ce(SO₄)₂). m.p. 168°-169°.[α]_(D) =+4.07 in CH₃ OH at c 0.50% g/100 mL.

EXAMPLE 115 1S-(1α,2α,3α,4α)]-₂-[[3-[4-[(5-Hydroxy-5-methyl-hexyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-2.2.1]hept-₂ -yl]methyl]benzenepropanoic acid

A. 5-Methyl-1,5-hexanediol

To 67 mL of a 3.0M solution of methylmagnesium bromide (201 mmol inether) stirring at 0° C. under argon, was added dropwise a solution ofvalerolactone (5.0 g, 50 mmol) in 25 mL dry THF. A white precipitate wasformed. After 30 minutes the reaction mixture was warmed up to roomtemperature. After 4.5 hours, the reaction was quenched with 12 mL ofwater and concentrated on a rotoevaporator. The residue was stirred with50 mL EtOAc and 20 mL saturated aqueous NH₄ Cl. The 2 layers wereseparated. The aqueous layer was extracted twice more with EtOAc (50 mLeach). The organic layers were combined and washed with brine, driedover MgSO₄, and concentrated on a rotoevaporator to obtain 5.57 g (84%)of the title product. R_(f) is 0.35 in EtOAc; UV, Ce(SO₄)₂.

¹³ C NMR (67.8 MHz, CDCl₃) δ 70.8, 62.2, 43.2, 32.9, 29.2, 20.3.

B. 1,3-Dihydro-α,α-dimethyl-1,3-dioxo-2H-indole-₂ -pentanol

To a stirred solution of 1.50 g (11.3 mmol) of Part A compound, 2.08 g(14.2 mmol) of phthalimide and 3.93 g (15.0 mmol) of triphenylphosphinein 30 mL of dry CH₂ Cl₂ at 0° C. under argon, was added slowly 2.93 mL(3.0 g, 15.0 mmol) of DIAD. After the addition, the reaction mixture waswarmed up to room temperature. The reaction mixture was concentrated ona rotoevaporator. The residue was chromatographed eluting with 60:40hexane-EtOAc to obtain 2.47 g (83%) of the title product. R_(f) =0.2 in1:1 hexane-EtOAc; UV, Ce(SO₄)₂.

¹³ C NMR (67.8 MHz, CDCl₃): δ 168.0, 133.5, 131.3, 122.5, 69.7, 42.4,37.2, 28.4, 27.9, 21.0.

C. 6-Amino-₂ -methyl-₂ -hexanol, monohydro-chloride

A solution of 3.24 g (12.4 mmol) of Part B compound in 100 mL of dry CH₂Cl₂ under argon was cooled in an ice bath and stirred at 0° C. 1.57 mL(1.59 g, 49.6 mmol) of anhydrous hydrazine was added dropwise, and themixture was stirred for 16 hours. A white precipitate was formed. Thereaction mixture was concentrated on a rotoevaporator. The excess ofhydrazine was removed by concentrating the residue with 50 mL of toluenetwice. The residue (white precipitate) was dissolved in 180 mL of CH₃ OHand refluxed for 16 hours. A solution of 2 mL concentrated HCl in 8 mLof CH₃ OH was added as the reaction mixture was slowly cooled to roomtemperature. A white precipitate was formed. This was filtered off, andthe filtrate was concentrated to a yellow solid of 1.80 g (79%).

¹³ C NMR (67.8 MHz, CDCl₃) δ 69.0, 43.1, 29.3, 27.7, 22.1, 21.1.

D. [1S-(1α,2α,3α,4α)]-₂-[[3-4-[[(5-Hydroxy-5-methylhexyl)amino]carbonyl]-₂-oxa-zolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid,methyl ester

To a stirred solution of Part C compound (0.11 g, 0.66 mmol) in 3 mL ofmethylene chloride at 0° C. under argon, was added first C₂ H₅)₃ N (0.10g, 1.0 mmol), then 0.51 mmol of acid chloride prepared as in Example 2,Part J as a solution in 2 mL of methylene chloride. The reaction mixturewas slowly warmed to room temperature. After stirring for 5 hours atroom temperature, water was added, and the reacticn mixture wasextracted with methylene chloride (25 mL) 3 times. The organic layerswere combined and washed with brine, dried over MgSO₄, and concentratedto obtain an oil. This oil was crystallized from EtOAc/hexane to obtain0.25 g (100%) of a white solid.

¹³ C NMR (CDCl₃) δ 172.9, 163.6, 160.4, 140.4, 138.2, 137.5, 135.9,129.4, 128.7, 126.4, 126.2, 79.5, 78.4, 69.3, 51.4, 49.7 46.6, 43.0,38.6, 34.6, 32.1, 29.8, 29.6, 29.0, 28.6, 27.3, 21.3.

E. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[(5-Hydroxy-5-methylhexyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid

A solution of Part D ester (0.25 g, 0.50 mmol) in 3 mL of CH₃ OH, 1 mLof 1N NaOH, and 3 mL of THF at room temperature was stirred for 16hours. The reaction mixture was acidified with 10% aqueous HCl to pH 1and extracted with EtOAc (three times, 50 mL each). The organic layerswere combined, washed with brine, dried over MgSO₄, and concntrated toobtain a white solid. This was crystallized from EtOAc/hexane to obtain0.21 g (88%) of a solid. m.p. 149°-150° C. R_(f) is 0.16 in 0.5% CH₃COOH, 5% CH₃ OH, 94.5% EtOAc; UV, Ce(SO₄)₂. [α]_(D) =+1.49° at c 0.67 g/100 mL of CH₃ OH at room temperature.

EXAMPLE 116 [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(5-Carboxy-5-methyl-hexyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-[2.2.1]hept-₂ -yl]methyl]benzenepropanoic acid

A. 2,2-Dimethylpentanedioic acid, 5-methyl ester

A solution of 5.0 g (35.1 mmol) of 2,2-dimethyl glutaric anhydride in 10mL of CH₃ OH was stirred under argon. This reaction mixture was heatedslowly to 100° C. and stirred for 1 hour. The reaction mixture was thencooled and concentrated on the rotoevaporator to obtain 6.13 g (100%) oftitle compound in the form of a yellow oil. R_(f) is 0.7 in EtOAc; UV,Ce(SO₄)₂.

¹³ C NMR (67.8 MHz, CDCl₃) δ 175.0, 167.0, 51.5, 41.5, 38.8, 35.2, 25.5.

B. Tetrahydro-3,3-dimethyl-₂ H-pyran-₂ -one

To a solution of 6.13 g (35.2 mmol) of Part A compound in 50 mL THF and25 mL ₂ -propanol at 0° C. under argon, was added slowly 1.92 g (88.0mmol) of LiBH₄. This was then warmed to room temperature and stirred for18 hours. The reaction mixture was cooled in an ice bath and quenchedslowly with 25 mL of water and concentrated HCl until the pH was 1.5.This mixture was concentrated on the roto-evaporator to remove theorganic solvent. The remaining aqueous mixture was stirred with 50 mLCHCl₃, a white precipitate was filtered, and the organic layer wasseparated. The aqueous layer was extracted twice more with (25 mL each)CHCl₃ The organic layers were combined, washed with brine, dried overMgSO₄, and concentrated on the rotoevaporator to obtain 4.08 g of aclear oil. This was flash chromatographed eluting with gradient 0%-50%EtOAc in hexane to obtain 1.05 g of title compound and 3.0 g of thealcohol acid (seco-title compound).

¹³ C NMR (67.8 MHz, CDCl₃): δ 177.0, 70.4, 38.6, 34.9, 27.6, 20.5.

C. 5-Bromo-2,2-dimethylpentanoic acid

To a solution of 1.05 g (8.2 mmol) of Part B compound in 13 mL of 48%HBr was added 0.33 mL of concentrated H₂ SO₄. The reaction mixture wasrefluxed at 120° C. for 3 hours, then cooled and extracted three timeswith CHCl₃ (25 mL each). The organic layers were combined, washed withbrine, dried over MgSO₄ and concentrated to obtain 1.44 g (84%) of ayellow oil.

¹³ C NMR (67.8 MHz, CDCl₃): δ 184.4, 41.7, 38.9, 33.6, 28.4, 24.9.

D. 5-Bromo-2,2-dimethylpentanoic acid, methyl ester

To a solution of 1.44 g (6.89 mmol) of Part C compound in 5 mL of CH₃OH, was added (0.73 mL, 0.81 g, 10.3 mmol) acetyl chloride, and thereaction mixture was stirred for 18 hours at room temperature. Thereaction mixture was neutralized to pH 7 with triethylamine andconcentrated on a rotoevaporator to obtain a semisolid. The solid wasfiltered, washed with ether, and the filtrate was concentrated to obtain1.5 g (98%) of title compound in the form of an orange oil. R_(f) is0.98 in 1:1 hexane-EtOAc; UV, Ce(SO₄)₂.

E. 5-Cyano-2,2-dimethylpentanoic acid, methyl ester

A solution of 1.50 g (6.72 mmol) of Part D compound in 10 mL of ethanolwas added to a solution of 2.18 g (33.6 mmol) of KCN in 3 mL of water.The resulting homogeneous reaction mixture was stirred for 21/2 days atroom temperature. To the reaction mixture was added 50 mL of EtOAc and 8mL of H₂ O to form two layers. The organic layer was separated, and theaqueous layer was extracted twice more with EtOAc (50 mL each). Theorganic layers were combined, washed with brine, dried over MgSO₄, andconcentrated on the rotoevaporator to obtain 0.88 g (78%) of titlecompound in the form of a yellow oil.

F. 6-Amino-2,2-dimethylhexanoic acid, methyl ester, monohydrochloride

To a solution of 0.44 g (2.60 mmol) of Part E compound in 3 mL of CH₃OH, at room temperature was added 1 mL of acetyl chloride, and thereaction mixture was stirred for 15 minutes. To the above mixture, 0.09g of PtO₂ was added, and a hydrogen balloon was attached. The reactionmixture was stirred at room temperature for 16 hours, then filteredthrough a Celite pad. The filter cake was washed three times with CH₃OH, and the filtrate was concentrated to obtain title compound in theform of a yellow oil of 0.46 g (84%), which solidified in the freezer.

¹³ C NMR (67.8 MHz, CDCl₃): δ 177.9, 51.6, 41.9, 39.7, 27.7, 24.9, 22.0.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5-Carboxy-5-methylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, methyl ester

To a stirred solution of Part F compound (0.12 g, 0.57 mmol) in 3 mL ofmethylene chloride at 0° C. under argon, was added first triethylamine(0.10 g, 1.0 mmol), then 0.51 mmol of acid chloride prepared as inExample 2, Part J as a solution in 2 mL of CH₂ Cl₂. The reaction mixturewas slowly warmed to room temperature. After stirring for 18 hours atroom temperature, water was added, and the reaction mixture wasextracted with methylene chloride (25 mL). The aqueous layer wasextracted twice more with CH₂ Cl₂ (25 mL). The organic layers werecombined, washed with brine, dried over MgSO₄, and concentrated toobtain title compound in the form of a yellow solid of 0.20 g (71%).R_(f) =0.8 in 5% CH₃ OH/95% EtOAc; UV, Ce(SO₄)₂.

H. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[(5-Carboxy-5-methylhexyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-methyl]benzenepropanoic acid

A solution of Part G ester (0.20 g, 0.37 mmol) in 2 mL of CH₃ OH, 1 mLof 1NNaOH, and 2 mL of THF at room temperature was stirred for 2.5 days.The reaction mixture was acidified with 10% HCl to pH 1, and extractedthree times with EtOAc (25 mL each). The organic layers were combined,washed with brine, dried over MgSO₄, and concentrated to obtain a whitesolid. This was crystallized from EtOAc/hexane to obtain 0.10 g (53%) oftitle compound in the form of a solid.

m.p. 123°-125° C. R_(f) is 0.7 in 0.5% CH₃ CO₂ H, 10% CH₃ OH, 89.5%EtOAc; UV, Ce(SO₄)2. [α]° D=+5.4° at c 0.26 g/100 mL of CH₃ OH at roomtemperature.

EXAMPLE 117 [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-(Aminocarbonyl)-₂-oxa-zolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid

A. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-(Amino-carbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of 200 mg (0.52 mmol) of acid prepared as in Example 2,Part J in 10 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 smalldrop of DMF, followed by 310 μL (0.62 mmol, 2M/CH₂ Cl₂, Aldrich) ofoxalyl chloride solution. The reaction was stirred at room temperatureuntil gas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo and azeotroped with two-5 mL portions of tolueneto give the crude acid chloride as a pale yellow solid.

To a solution of 0.14 mL (1.6 mmol, 11M) methanolic ammonia, stirred at-30° C., was added dropwise over 10 minutes a solution of crude acidchloride in 10 mL dry CH₂ Cl₂ (distilled from P₂ O₅). The reaction wasstirred at room temperature for 1 hour, then the mixture was partitionedbetween 40 mL ethyl acetate and 40 mL lM HCl. The organic layer wasseparated; the water layer was extracted with two-15 mL portions ofethyl acetate. The combined ethyl acetate layers were dried (MgSO₄) andconcentrated in vacuo to give 120 mg (0.32 mmol, 62%) of title amide asa white solid.

B. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-(Amino-carbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-₂-yl]methyl]benzenepropanoic acid

To a solution of 120 mg (0.32 mmol) of Part A ester in 4 mL distilledTHF/1 mL water was added 27 mg (0.65 mmol, Aldrich) of lithium hydroxidemono-hydrate. The reaction was stirred vigorously for 3.5 hours at roomtemperature, then quenched by the addition of 1.3 mL (1.3 mmol) 1M HCl.The mixture was partitioned between 30 mL ethyl acetate and 30 mL water;the water layer was separated and extracted with two-15 mL portions ofethyl acetate. The combined ethyl acetate layers were dried (MgSO₄) andconcentrated in vacuo to give a crude white solid. The crude solid wasrecrystallized from hot methanol to give 70 mg (0.19 mMol, 61%) of titleacid as a white solid, mp >200° C.

IR (KBr): 3443, 3288, 3107, 2982, 2953, 1709, 1664, 1608 cm⁻¹.

MS(CI): 371 (M+H)⁺.

OR: [α]_(D) =+11° (c=0.25 in DMSO).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.20, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₂₀ H₂₂ N₂ O₅ :

C, 64.85; H, 5.99; N, 7.56

Found: C, 64.74; H, 6.16; N, 7.34.

EXAMPLE 118 1S-(1α,2α(E),3α,4α)]-3-[₂-[[3-[[(4-Cyclohexyl-butyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-2.2.1]hept-₂ -yl]methyl]phenyl]-₂ -propenoicacid

A. [1S-(1α,2α,3α,4α)]-₂-[[3-[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]methyl]-7-oxabicyclo[2.2.1]hept-₂-yl]methyl]benzenepropanoic acid methyl ester

To a stirred mixture of alcohol prepared in Example 1, Part J (1.32 g,4.34 mmol) in 20 mL of dry CH₂ Cl₂ under argon was added sequentiallytriethylamine (0.91 mL, 6.51 mmol) and chlorodimethylthexyl silane (1.02mL, 5.21 mmol). This mixture was stirred at room temperature for 22hours at which time 100 mg of N,N-dimethylaminopyridine was added. Themixture was stirred at room temperature for 2.5 hours and diluted with400 mL of EtOAc. The resulting mixture was washed with 1N HCl solution(3×40 mL), saturated NaHCO₃ solution (1×40 mL) and brine (1×40 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was chromatographed on 100 g of Merck silica gel 60 using 4:1hexane-ether as eluant to give 1.54 g (87%) of title silyl ether.

TLC: silica gel, 4:1 hexane-ether, R_(f) 0.52, Ce(SO₄)₂.

B. [1S-(1α,2α,3α,4α)]-₂-[[3-[[[Dimethyl-(1,1,2-trimethylpropyl)silyl]oxy]methyl]-7-oxabicyclo[2.2.1]hept-₂-yl]methyl]-α-(phenyl-seleno)benzenepropanoic acid, methyl ester

To a stirred mixture of dry diisopropylamine (1.80 mL, 12.8 mmol) in 30mL of dry THF under argon at -78° C. was added 2.5M solution ofn-butylLi in hexane (4.67 mL, 11.7 mmol) over 2 minutes. This mixturewas stirred at -78° C. under argon for 50 minutes at which time asolution of Part A silyl ether (2.82 g, 6.32 mmol) in 20 mL of dry THFwas added dropwise over 10 minutes. This mixture was stirred at -78° C.under argon for 30 minutes. To this mixture was added a solution ofdiphenyl diselenide (3.64 g, 11.7 mmol) in 10 mL of dry THF over 5minutes. This mixture was stirred at -78° C. for 30 minutes and at roomtemperature for 30 minutes. The mixture was quenched slowly by theaddition of 60 mL of saturated NH₄ Cl solution. The aqueous layer wasseparated and extracted with ether (4×100 mL). The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 170 g of Mercksilica gel 60 using 4:1 hexane-ether as eluant to give 2.81 g (74%) oftitle selenide. TLC: silica gel, 4:1 hexane-ether, R_(f) 0.54, Ce(SO₄)₂.

¹³ C of title compound (67.5 Mz, CDCl₃): δ 172.8, 139.7, 139.7, 136.6,135.8, 129.8, 129.3, 129.0, 128.6, 128.0, 126.9, 126.1, 79.2, 61.6,52.0, 49.5, 46.8, 46.4, 43.7, 43.2, 35.1, 34.3, 34.2, 31.6, 30.2, 29.6,29.4, 25.1, 22.6, 20.4, 20.4, 20.1, 18.6, 14.1, -1.5, -3.4.

C. [1S-[1α,2α(E),3α,4α]]-3-[₂-[[3-[[[Di-methyl(1,1,2-trimethylpropyl)silyl]oxy]-methyl]-7-oxabicyclo[2.2.1]hept-₂-yl]-methyl]phenyl]-2-propenoic acid, methyl ester

To a stirred mixture of Part B selenide (2.81 g, 4.67 mmol) in 28 mL ofEtOAc and 18 mL of CH₃ OH was added 4 mL of 30% H₂ O₂. The mixture wasstirred at room temperature for 1 hour and diluted with 400 mL of EtOAc.The resulting mixture was washed once with 50 mL of brine, dried(MgSO₄), filtered and concentrated in vacuo. This was chromatographed on120 g of Merck silica gel 60 using 4:1 hexane-ether as eluant to give1.13 g (55%) of title cinnamate. TLC: silica gel, 4:1 hexane-ether.R_(f) 0.54, vanillin.

¹³ C of title compound (67.5 Mz, CDCl₃): δ 167.2, 142.2, 141.3, 133.2,130.8, 130.0, 126.9, 126.6, 119.4, 79.3, 79.0, 61.8, 51.7, 49.5, 47.3,34.2, 31.2, 29.6, 29.3, 25.1, 20.1, 18.6, -3.4.

D. [1S-[1α,2α(E),3α,4α]]-3-[₂-[[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-₂-yl]methyl]-phenyl]-2-propenoic acid, methyl ester

To a stirred mixture of Part C cinnamate (1.12 g, 2.52 mmol) in 70 mL ofCH₃ OH was added 0.5 mL of acetyl chloride. This mixture was stirred atroom temperature for 2 hours and concentrated in vacuo. This waschromatographed on 24 g of Merck silica gel 60 using ₂ % CH₃ OH in CH₂Cl₂ as eluant to give 510 mg (67%) of title alcohol. TLC: silica gel, 2%CH₃ OH/CH₂ Cl₂ R_(f) 0.24, Ce(SO₄)₂.

¹³ C of title compound (67.5 Mz, CDCl₃): δ 167.4, 142.2, 141.2, 133.0,130.6, 126.7, 126.6, 119.0, 79.3, 79.1, 61.6, 51.7, 49.2, 47.5, 31.4,29.5, 29.3.

E. [1S-[α,2α(E),3α,4α]]-3-[₂ -[(3-Carboxy-7-oxabicyclo[2.2.1]hept-₂-yl)methyl]phenyl]-2-propenoic acid, methyl ester

To a stirred mixture of Part D alcohol (500 mg, 1.66 mmol) in 50 mL ofacetone was added MnSO₄ treated Jones Reagent (about 4 mL) until anorange-red color persisted. The mixture was stirred at room temperaturefor 2 hours and quenched with isopropyl alcohol (IPA). The mixture wasconcentrated in vacuo and partitioned between 80 mL of 3M NaHSO₃solution and EtOAc (4×100 mL). The combined EtOAc extracts were washedwith brine (2×80 mL), dried (MgSO₄), filtered and concentrated in vacuoto give 490 mg (94%) of title acid.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.11, Ce(SO₄)₂.

¹³ C of title compound (67.5 Mz, CDCl₃): δ 176.7, 167.3, 141.8, 139.7,133.0, 131.1, 130.0, 126.9, 126.8, 119.4, 78.5, 52.1, 51.7, 48.8, 32.9,29.2, 28.6.

F. [1S-[1α,2α(E),3α,4α]]-3-[₂ -[[3-[[[₂-(4-Cyclohexylbutyl)-1-(hydroxymethyl)-₂-oxo-ethyl]amino]carbonyl]-7-oxabicyclo2.2.1]-hept-₂ -yl]methyl]phenyl-₂-propenoic acid, methyl ester

To a stirred mixture of Part E acid (490 mg, 1.55 mmol),1-hydroxybenzotriazole monohydrate (262 mg, 1.55 mmol) and ₂-amino-n-(4-cyclohexyl-butyl)-3-hydroxypropanamide (500 mg, 2.07 mmol)in 30 mL of DMF under argon was added sequentially triethylamine (0.43mL, 3.10 mmol) and ethyl-3-(3-dimethyamino)propyl carbodiimidehydrochloride salt (287 mg, 1.55 mmol). This mixture was stirred at roomtemperature for 16 hours and concentrated in vacuo. The crude productwas diluted with 400 mL EtOAc and washed with 0.2N NaOH solution (1×60mL), 1NHCl solution (1×40 mL), saturated NaHCO₃ solution (1×20 mL) andbrine (1×40 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. Purification was effected by flash chromatographyon 50 g of Merck silica gel 60 using 0.35 L of each of ₂ % and 4% CH₃ OHin CH₂ Cl₂ as eluants to give 630 mg (75%) of title amide. TLC: silicagel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.44, Ce(SO₄)₂.

¹³ C of title compound (67.5 Mz, CDCl₃) δ 172.7, 170.6, 167.5, 141.9,140.1, 133.0, 130.9, 126.9, 119.2, 79.1, 62.8, 54.1, 51.8, 49.0, 39.6,37.4, 36.9, 33.2, 33.2, 29.7, 26.6, 26.3, 26.3.

G. [1S-[1α,2α(E),3α,4α]]-3-[₂-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂-yl]-methyl]ohenyl]-2-propenoic acid, methyl ester

To a stirred mixture of Part F amide (630 mg, 1.17 mmol) in 15 mL ofCHCl₃ under argon at 0° C. was added in order triethylamine (0.32 mL,2.30 mmol) and mesyl chloride (0.11 mL, 1.42 mmol). This mixture wasstirred at 0° C. for 10 minutes and at room temperature for 20 minutes.The mixture was concentrated in vacuo and diluted with 60 mL of acetone.To this mixture was added K₂ CO₃ (323 mg, 2.34 mmol). The mixture wasrefluxed under argon for 2 hours and cooled to room temperature. Thesolid was filtered off and rinsed with acetone (5×30 mL). The filtratewas concentrated in vacuo and chromatographed on 40 g of Merck silicagel 60 using 0.3 L of each of ₂ % and 4% CH₃ OH in CH₂ Cl₂ as eluants togive 610 mg of title oxazoline in a quantitative yield. TLC: silica gel,4% CH₃ OH in CH₂ Cl₂, R_(f) 0.54, Ce(SO₄)₂.

¹³ C of title compound (67.5 Mz, CDCl₃): δ 171.4, 169.0, 167.3, 141.8,140.1, 132.7, 130.8, 130.2, 127.0, 126.8, 119.1 79.0, 78.0, 70.1, 68.4,51.7, 49.6, 46.8, 39.2, 37.4, 37.0, 33.2, 33.2, 29.8, 28.5, 26.6, 26.3,26.3, 24.0.

H. [1S-(1α,2α(E),3α,4α)]-3-[₂ -[3-[[(4-Cyclohexylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]phenyl]-2-propenoicacid, methyl ester

To a stirred mixture of CuBr₂ (557 mg, 2.49 mmol) in 6 mL of EtOAc underargon was added DBU (0.75 mL, 4.99 mmol). The mixture was stirred atroom temperature for 20 minutes. To this dark brown mixture was thenadded a solution of Part G oxazoline (610 mg, 1.20 mmol) in 6 mL ofCHCl₃ The reaction mixture was stirred at room temperature for 16 hoursat which time CuBr₂ (560 mg, 2.49 mmol) and DBU (0.38 mL, 2.50 mmol)were added. The mixture was stirred for 8 hours. To this mixture wasagain added CuBr₂ (280 mg, 1.25 mmol) and DBU (0.38 mL, 2.50 mmol). Themixture was stirred at room temperature for 16 hours at which time oncemore CuBr₂ (280 mg, 1.25 mmol) and DBU (0.38 mL, 2.50 mmol) were added.The reaction mixture was stirred at room temperature for another 7 hoursand poured into a solution of 100 mL of EtOAc and 100 mL of 1:1concentrated NH40H solution and saturated NH₄ OH solution. The aqueouslayer was separated and extracted with EtOAc (3×100 mL). The combinedEtOAc extracts were dried (MgSO₄), filtered and concentrated in vacuo.This was chromatographed on 40 g of Merck silica gel 60 using ₂ % CH₃ OHin CH₂ Cl₂ as eluant to give 381 mg (63%) of title oxazole. TLC: silicagel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.74, Ce(SO₄)₂.

⁻⁻ C of title compound (67.5 Mz, CDCl₃) δ 167.3, 163.5, 160.5, 141.9,140.5, 139.7, 136.3, 133.0, 130.6, 130.0, 126.9, 119.3, 79.5, 78.4,51.7, 50.6, 46.9, 39.1, 37.5, 37.0, 33.3, 33.3, 29.9, 28.6, 26.6, 26.3,26.3, 24.2.

I. [1S-(1α,₂ o(E),3α,4α)]-3-[₂-[[3-[[(4-Cyclohexylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]phenyl]-2-propenoic acid

To a stirred mixture of Part H oxazole (375 mg, 0.72 mmol) in 10 mL ofTHF and 12 mL of CH₃ OH was added 5 mL of 1N NaOH solution. This mixturewas stirred vigorously at room temperature for 5 hours and concentratedin vacuo to remove the organic solvents. The mixture was acidified to pH2 by the addition of 1NHCl solution, saturated with NaCl and extractedwith EtOAc (4×40 mL). The combined EtOAc extracts were dried (MgSO₄),filtered and concentrated in vacuo. The crude acid was recrystallized in1% CH₃ OH/EtOAc and hexane at -5° C. to give 280 mg (77%) of pure titleacid, m.p. 210°-211° C. TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f)0.13, Ce(SO₄)₂.

¹³ C NMR title compound CDCl₃ +CD₃ OD, 67.5 MHz): δ 170.9, 168.6, 163.8,141.9, 140.7, 139.1, 135.7, 132.9, 130.3, 129.8, 126.8, 119.9, 79.8,78.6, 50.0, 46.6, 39.2, 39.0, 37.3, 36.9, 33.2, 33.1, 33.1, 29.4, 28.6,26.4, 26.1, 26.1, 24.0.

EXAMPLE 119[1S-(1α,2α,3α,4α)-2-[[3-[4-[[[2-(4-Fluorophenyl)-1,1-dimethylethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A. 3-(4-Fluorophenyl)propionic acid, methyl ester

To 35 mL of methanol (Burdick and Jackson) cooled in an ice-bath wasaded dropwise over several minutes 3.5 mL of acetyl chloride(Mallinckrodt). The solution was stirred for 10 minutes then 3.00 g(17.9 mmol, Trans World Chemicals) of 3-(4-fluorophenyl)propionic acid,was added. The reaction mixture was stirred at 0° C. for 6 hours thenconcentrated in vacuo. The residue was dissolved in 25 mL of ether,dried (magnesium sulfate) and concentrated in vacuo to give 3.08 g (16.9mmol, 95%) of title ester as a colorless liquid.

B. 4-Fluoro-α,α-dimethylbenzenepropanoic acid, methyl ester

To a solution of 3.2 mL (23 mmol, distilled from calcium hydride) ofdiisopropylamine in 30 mL of dry THF (distilled fromsodium/benzophenone) cooled to -78° C. was added dropwise 8.5 mL (2.5Min hexane, 21 mmol, Aldrich) of n-butyllithium solution over 10 minutes.The resulting solution was stirred for 20 minutes then a solution of 3.1mL (18 mmol, Aldrich) of sieve-dried hexamethyl-phosphoramide (HMPA) in3 mL of THF was added rapidly followed by the dropwise addition over 10minutes of a solution of 3.0 g (16.5 mmol) of Part A ester in 10 mL ofdry THF. The reaction mixture was stirred for 20 minutes then addeddropwise was 1.6 mL (26 mmol, filtered through basic alumina) ofiodomethane over about 2 minutes. The reaction was stirred at -78° C.for 30 minutes then warmed to 0` C., quenched with 5 mL of 1M aqueousHCl solution and partitioned between 200 mL of 1M aqueous HCl and 60 mLof 1:1 ethyl acetate/hexane. The organic layer was separated, washedwith 200 mL of 1M aqueous HCl, 200 mL of water, 100 mL of 1:1 3M aqueoussodium bisulfide/brine solution, dried (magnesium sulfate) andconcentrated in vacuo to give the crude monoalkylation product as anoil. The alkylation procedure was repeated as described above and thecrude dialkylation product was purified by flash chromatography (Mercksilica, 20×5.0 cm, 1:20 ethyl acetate/hexane) to afford 2.15 g (10.2mmol, 62%) of title ester as a colorless oil.

C. 4-Fluoro-α,α-dimethylbenzenepropanoic acid

A mixture of 2.10 g (10.0 mmol) of Part B ester and 4.2 g (100 mmol,Aldrich) of lithium hydroxide monohydrate in 30 mL of 3:2:1 ofp-dioxane/methanol/water was stirred rapidly at 65° C. for 4 hours. Thereaction was cooled then concentrated in vacuo to give an oil. To theoil was added 50 mL of 1M aqueous HCl solution then concentrated HCl(about 5 mL) was added until pH<1. The resulting mixture was extractedwith two-50 mL portions of ether. The ether extracts were combined,dried (magnesium sulfate) and concentrated in vacuo to give 1.85 g (9.44mmol, 94%) of crude acid as an oil.

D. 1-Fluoro-4-(2-isocyanato-2-methyl-propyl)benzene

To a solution of 1.80 g (9.18 mmol) of Part C acid in 20 mL of t-butanol(distilled from sodium) was added at room temperature 1.02 g (10.1 mmol,distilled from calcium hydride) of triethylamine then 2.78 g (10.1 mmol,Aldrich) of diphenylphosphoryl azide. The resulting solution was heatedto reflux (about 90° C.) for 20 hours. The reaction mixture was cooledthen concentrated in vacuo to give an oil. The crude oil was purified byflash chromatography (Merck silica, 10×5.0 cm, 1:10 ethylacetate/hexane) to afford 1.31 g (6.79 mmol, 74%) of title isocyanate asa colorless oil.

E. [2-(4-Fluorophenyl)-1,1-dimethylethyl]-carbamic acid, phenylmethylester

A solution of 1.30 g (6.74 mmol) of Part D isocyanate and 2.0 mL (19mmol, Aldrich) of benzyl alcohol was heated to 100° C. for 20 hours. Thereaction mixture was cooled and purified by flash chromatography (Mercksilica, 12×5.0 cm, 1:8 ethyl acetate/hexane) to afford 1.62 g (5.38mmol, 80%) of title compound as a colorless oil.

F. 4-Fluoro-α,α-dimethylbenzeneethanamine, monohydrochloride

A mixture of 1.60 g (5.32 mmol) of Part E carbamate and 160 mg of 10%palladium on activated carbon catalyst (Aldrich) in 15 mL of methanol(Burdick and Jackson) was stirred rapidly under an atmosphere ofhydrogen (balloon) for 1.5 hours. The reaction mixture was passedthrough a 0.4 μM polycarbonate membrane then the filtrate was cooled inan ice-bath and 10 mL of acidic methanol was added (prepared by additionof 1 mL of acetyl chloride to 10 mL of methanol at 0° C). The resultingsolution was concentrated in vivo to give a solid. The crude solid wasdissolved in several milliliters of methanol then ether was added. Thesolid which precipitated was collected on a Buchner funnel, washed withadditional ether then dried under oil pump vacuum to give 945 mg (4.64mmol, 87%) of title amine hydrochloride as small white flakes, mp189°-190° C.

G.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-Fluorophenyl)-1,1-dimethylethyl]amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid, methyl ester

To a solution of of 200 mg (0.52 mmol) of oxazole acid prepared as inExample 2, Part J in 3 mL of dry methylene chloride (distilled fromphosphorous pentoxide) was added at room temperature a small drop of DMFthen 55 μL (0.63 mmol, Aldrich) of oxalyl chloride. The solution wasstirred until gas evolution ceased, about 20 minutes, then concentratedin vacuo to give the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.52 mmol) in 4 mL ofdry methylene chloride cooled in an ice-bath was added 210 μL (1.5 mmol,distilled from calcium hydride) of triethylamine followed by 136 mg(0.67 mmol) of Part F amine hydrochloride. The reaction mixture wasstirred for 30 minutes. The resulting solution was partitioned between20 mL of 1M aqueous HCl solution and 20 mL of ethyl acetate. The organiclayer was separated, dried (magnesium sulfate) and concentrated in vacuoto give an oil. The crude material was purified by flash chromatography(Merck silica, 10×3.0 cm, ethyl acetate) to afford 275 mg (0.51 mmol,98%) of title ester as a colorless oil.

H.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-Fluorophenyl)-1,1-dimethylethyl]amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid

A mixture of 270 mg (0.51 mmol) of Part G ester and 84 mg (2.0 mmol,Aldrich) of lithium hydroxide monohydrate in 3 mL of 2:1 THF/water wasstirred rapidly at room temperature for 3 hours then partitioned between20 mL of 1M aqueous HCl solution and 20 mL of ethyl acetate. The organiclayer was separated, dried (magnesium sulfate) and then concentrated invacuo to give an oil. The crude material was purified by flashchromatography (Merck silica, 12×1.5 cm, 1:9 methanol/methylenechloride) to afford 233 mg (0.45 mmol, 88%) of title acid as a solidwhite foam, mp 68° C. (softens).

IR(KBr): 3435, 2978, 1719, 1657, 1599, 1508, 1219, 1159 cm⁻¹.

MS(CI): 521 (M+H)⁺.

OR: [α]_(D) =+22° (c=0.5 in chloroform)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.53, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₀ H₃₃ FN₂ O₅ :

C, 69.21; H, 6.39; N, 5.38; F, 3.65;

Found: C, 68.80; H, 6.25; N, 5.18; F, 3.63.

EXAMPLE 120[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-Fluorophenyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A. 4-Fluorobenzenepropanol

To a solution of 5.00 g (29.8 mmol, Trans World Chemicals) of3-(4-fluorophenyl)propionic acid in 20 mL of dry THF (distilled fromNa/benzophenone) cooled in an ice-bath was added dropwise 40 mL (1.0M inTHF, 40 mmol, Aldrich) of borane-tetrahydrofuran solution over 30minutes. The solution was allowed to warm to room temperature thanstirred for 18 hours. The reaction mixture was quenched by slow additionof about 5 mL of water then concentrated in vacuo. The oily residue waspartitioned between 50 mL of 1M aqueous NaOH solution and 50 mL of ethylacetate. The organic layer was separated, washed with 50 mL of water,dried (magnesium sulfate) and concentrated in vacuo to afford 4.50 g(29.2 mmol, 98%) of crude title alcohol as a pale yellow liquid.

B. 4-Fluorobenzenebutanenitrile

To a solution of 4.45 g (28.9 mmol) of Part A alcohol and 4.2 mL (42mmol, distilled from calcium hydride) of triethylamine in 30 mL of drymethylene chloride (distilled from phosphorous pentoxide) cooled to -20°C. was added dropwise over 5 minutes a solution of 2.7 mL (35 mmol,Aldrich) of methanesulfonyl chloride in 5 mL of methylene chloride. Thereaction mixture was stirred for 15 minutes then partitioned between 30mL of methylene chloride and 50 mL of 1M aqueous HCl solution. Theorganic layer was separated then washed with 50 mL of 1M aqueous HClsolution, 50 mL of saturated aqueous sodium bicarbonate solution, dried(magnesium sulfate) and concentrated in vacuo to give the crude mesylateas an oil. A mixture of the crude mesylate and 3.76 g (57.8 mmol,Mallinckrodt) of potassium cyanide in 50 mL of DMSO (Burdick andJohnson) was heated to 80° C. for 1.5 hours. The resulting gel wascooled to room temperature then partitioned between 200 mL of water and100 mL of 1:1 ethyl acetate/hexane. The organic layer was separated,washed with two-200 mL portions of water, 100 mL of brine, dried(magnesium sulfate) and concentrated in vacuo to give a liquid. Thecrude material was purified by flash chromatography (Merck silica,10×5.0 cm, 1:4 ethyl acetate/hexane) to afford 4.17 g (25.6 mmol, 89%)of title nitrile as a colorless liquid.

C. 4-Fluorobenzenebutanamine, monohydrochloride

To a solution of 4.10 g (25.2 mmol) of Part B nitrile in 40 mL of dryether (distilled from Na/benzophenone) cooled to 0° C. was added a total1.00 g (26 mmol, Aldrich) of lithium aluminum hydride in severalportions. The reaction mixture was stirred at 0° C. for 2 hours then atroom temperature for 24 hours. The resulting mixture was cooled in anice-bath then quenched by slow, successive addition of 1.0 mL of water,1.0 mL of 15% of aqueous NaOH solution, then 3.0 mL of water. After 30minutes the slurry was filtered to remove precipitated aluminum salts.The salts were washed with additional ether. The filtrate was collectedand acidified by addition of 50 mL of methanolic HCl (prepared byaddition of 3.5 mL of acetyl chloride to 50 mL of methanol at 0° C.).The solution was concentrated in vacuo to give a gummy white solid. Thecrude material was recrystallized (ether/ methanol) to afford 2.95 g(14.5 mmol, 58%) of title amine hydrochloride as a white solid.

D. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[[4-(4-Fluorophenyl)butyl]amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid,methyl ester

To a solution of 200 mg (0.52 mmol) of oxazole acid prepared as inExample 2, Part J in 3 mL of dry methylene chloride (distilled fromphosphorous pentoxide) was added at room temperature a small drop of DMFthen 55 μL (0.63 mmol, Aldrich) of oxalyl chloride. The solution wasstirred until gas evolution ceased, about 20 minutes, then concentratedin vacuo to give the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (about 0.52 mmol) in 5 mL ofdry methylene chloride cooled in an ice-bath was added 200 μL (1.4 mmol,distilled from calcium hydride) of triethylamine followed by 142 mg(0.70 mmol) of Part C compound. The reaction mixture was stirred for 15minutes. The resulting solution was added to 20 mL of 1M aqueous HClsolution and extracted with two-15 mL portions of ethyl acetate. Theorganic layers were combined, dried (magnesium sulfate) and concentratedin vacuo to give a solid. The crude material was purified by flashchromatography (Merck silica, 12×1.5 cm, 4:2:1 ethyl acetate/hexane/methylene chloride) followed by recrystallization (ethyl acetate/hexane)to afford 201 mg (0.38 mmol, 73%) of title ester as a white solid, mp165°-166° C.

E. [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[4-(4-Fluorophenyl)butyl]amino]carbonyl]-₂-oxa-zolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid

A mixture of 175 mg (0.33 mmol) of Part D ester and 28 mg (0.67 mmol,Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/water wasstirred rapidly at room temperature for 2.5 hours then acidified byaddition of 1.5 mL of lM HCl solution. The resulting solution was addedto 20 mL of water then extracted with two-15 mL portions of ethylacetate. The combined organic layers were dried (magnesium sulfate) andthen concentrated in vacuo to give a solid. The crude material wasrecrystallized (ethyl acetate/hexane) to afford 140 mg (0.27 mmol, 82%)of title acid as small white crystals, mp 141°-143° C.

IR(KBr): 3408, 2940, 1709, 1651, 1601, 1510, 1219 cm⁻¹.

MS(CI): 521 (M+H)⁺.

OR: [α]_(D) =+20° (c=0.5 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.51, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Analysis Calc'd for C₃₀ H₃₃ FN₂ O₅ :

C, 69.21; H, 6.39; N, 5.38; F, 3.65;

Found: C, 69.12; H, 6.33; N, 5.35; F, 3.72.

EXAMPLE 121 [1S-(1α,2α,3α,4α)]-₂-[3-[4-[(2,2-Dimethylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-₂-yl]methyl]benzenepropanoic acid

A. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(2,2-Dimethylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid,methyl ester

To a stirred mixture of oxazole acid prepared in Example 2, Part J (92.1mg, 0.24 mmol) in 4 mL of dry CH₂ Cl₂ under argon at 0° C. was added onedrop of DMF and then added dropwise ₂ M solution of oxalyl chloride inCH₂ Cl₂ (0.14 mL, 0.29 mmol). The mixture was stirred at 0° C. for 10minutes and stirred at room temperature for 1 hour. The mixture wascooled to 0° C. Excess oxalyl chloride was removed. To this mixture wasadded a solution of Et₃ N (0.13 mL, 0.96 mmol) and 2,2-dimethylbutylamine hydrochloride salt (39.4 mg, 0.29 mmol, prepared by 1) treatmentof 2,2-dimethylbutyric acid chloride with concentrated NH₄ OH 2) amidewas reduced with LAH and worked up directly as a hydrochloride salt toprevent the loss of this volatile amine). The mixture was stirred at 0°C. for 20 minutes and at room temperature for 1 hour. The mixture wasdiluted with 100 mL of EtOAc and washed once with 20 mL of 1NHClsolution. The organic layer was dried (MgSO₄), filtered and concentratedin vacuo. This was chromatographed on 8 g of Merck silica gel 60 using1:1 EtOAc-hexane as eluant to give 50 mg (45%) of title ester.

TLC: silica gel, EtOAc, R_(f) 0.84, Ce(SO₄)₂.

¹³ C NMR of title compound (67.5 MHz, CDCl₃) δ: 173.0, 163.7, 160.7,140.7, 138.5, 137.8, 136.1, 129.7, 128.9, 126.6, 126.4, 79.6, 78.6,51.6, 50.0, 48.4, 47.0, 34.8, 34.7, 32.4, 32.1, 29.9, 28.9, 27.6, 24.4,8.3.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(2,2-Dimethylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid

To a stirred mixture of Part A ester (45 mg, 0.10 mmol) in 3 mL offreshly distilled THF was added 0.75 mL of water and LiOH monohydrate(12 mg, 0.29 mmol). The mixture was stirred at room temperature for 5hours and acidified to pH 2 by the addition of 1NHCl solution. Themixture was diluted with 10 mL of EtOAc and 5 mL of water, saturatedwith KCl and extracted with EtOAc (3×10 mL). The EtOAc extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification waseffected by flash chromatography on 6 g of Merck silica gel 60 using0.2% HOAc in 6% CH₃ OH/CH₂ Cl₂ as eluant to give 37 mg of acid. Thisacid was recrystallized in 3 mL of 1:5 EtOAc-hexane at -5° C. to give28.2 mg (65%) of pure title acid. m.p. 117°-119° C., TLC: silica gel,0.2% HOAc in 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.60, Ce(SO₄)₂.

¹³ C NMR of title compound (67.5 MHz, CDCl₃) δ: 177.0, 163.9, 161.0,141.2, 138.5, 137.8, 135.8, 129.6, 129.0, 126.7, 126.5, 79.6, 78.6,50.0, 48.5, 47.0, 34.8, 34.6, 32.4, 32.2, 29.9, 28.9, 27.4, 24.4% 8.2.

EXAMPLE 122 [1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[(2,2-Dimethylpropyl)-amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoic acid

A. t-Butylamide

To a solution of 20 mL of concentrated ammonium hydroxide and 40 mL ofTHF (distilled from sodium/benzophenone) cooled in an ice-bath was addeddropwise 12 mL (98 mmol, Aldrich) of trimethylacetyl chloride over ˜15minutes. The reaction mixture was stirred for 30 minutes thenpartitioned between 200 mL of water and 100 mL of ethyl acetate. Theorganic layer was separated, washed with 200 mL of saturated aqueoussodium bicarbonate solution, 100 mL of brine, dried (magnesium sulfate)and concentrated in vacuo to give a solid. The crude solid wasrecrystallized (ethyl acetate/hexane) to afford 2.20 g (21.8 mmol, 22%)of title amide as white flakes.

B. ₂ -(Trimethyl)ethylamine hydrochloride

To a solution of 2.00 g (19.8 mmol) of Part A amide in 20 mL of ether(distilled from sodium/ benzophenone) and 10 mL of THF (distilled fromsodium/benzophenone) cooled in an ice-bath was added in small portions atotal of 1.5 g (39 mmol, Aldrich) of lithium aluminum hydride. Thereaction mixture was stirred at 0° C. for 1 hour then at roomremperature for 48 hours. The resulting mixture was cooled in anice-bath then quenched by slow, successive addition of 1.5 mL of water,1.5 mL of 15% aqueous sodium hydroxide solution and 4.5 mL of water andstirred for 30 minutes. The slurry which formed was filtered. Thealuminum salts were washed with additional ether then the filtrate wasadded to 40 mL of acidic methanol (prepared by addition of 4 mL ofacetyl chloride to 40 mL of methanol). The solution was concentrated invacuo to give a solid. The crude solid was purified by recrystallization(ether/ methanol) to afford 950 mg (7.69 mmol, 39%) of title aminehydrochloride as white needles, m.p.>270°.

C. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(2,2-Dimethylpropyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid,methyl ester

To a solution of 150 mg (0.39 mmol), of oxazole acid prepared asdescribed in Example 2, Part J in 3 mL of dry methylene chloride(distilled from phosphorous pentoxide) was added at room temperature asmall drop of DMF then 45 μL (0.51 mmol, Aldrich) of oxalyl chloride.The solution was stirred until gas evolution ceased, ˜30 minutes, thenconcentrated in vacuo to give the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (˜0.39 mmol) in 3 mL of drymethylene chloride cooled in an ice-bath was added 140 μL (1.0 mmol,distilled from calcium hydride) of triethylamine followed by 58 mg (0.47mmol, Aldrich) of Part B amine hydrochloride. The reaction mixture wasstirred for 30 minutes then partitioned between 25 mL of lM aqueous HClsolution and 25 mL of ethyl acetate. The organic layer was separated,dried (magnesium sulfate) and concentrated in vacuo to give a solid. Thecrude material was recrystallized (ethyl acetate/hexane) to afford 138mg (0.30 mmol, 78%) of title ester as white crystals, m.p. 113°-115°.

D. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(2,2-Dimethylpropyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid

A mixture of 132 mg (0.29 mmol) of Part C ester and 50 mg (1.2 mmol,Aldrich) of lithium hydroxide monohydrate in 4.5 mL of 2:1 THF/water wasstirred rapidly at room temperature for 3 hours then acidified byaddition of 2.4 mL of 1M aqueous HCl solution. The resulting solutionwas partitioned between 20 mL of water and 25 mL of ethyl acetate. Theorganic layer was separated, dried (magnesium sulfate) and thenconcentrated in vacuo to give a solid foam. The crude material wasrecrystallized (ethyl acetate/hexane) to afford 116 mg (0.26 mmol, 91%)of title compound as white crystals, mp 172°-173°.

IR(KBr): 3418, 2956, 1720, 1602, 1527, 1205, 1104 cm⁻¹.

MS(CI): 441 (M+H)⁺.

OR: [α]_(D) =+39° (c=0.25 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.48, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Anal. Calc'd for C₂₅ H₃₂ N₂ O₅ +0.25 EtOAc:

C, 67.51; H, 7.41; N, 6.06;

Found: C, 67.25; H, 7.44; N, 5.96.

EXAMPLE 123 [1S-1α,2α,3α,4α)]-₂-[[3-[4-[[(3,3-Dimethylbutyl)-amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]-hept-₂ -yl]methyl]benzenepropanoic acid

A. [1S-(1α,2α,3α,4α)]-₂ -[[3-4-[[(3,3-Dimethylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid,methyl ester

To a solution of 200 mg (0.52 mmol) of oxazole acid prepared asdescribed in Example 2, Part J in 3 mL of dry methylene chloride(distilled from phosphorous pentoxide) was added at room temperature asmall drop of DMF then 55 μL (0.63 mmol, Aldrich) of oxalyl chloride.The solution was stirred until gas evolution ceased, ˜20 minutes, thenconcentrated in vacuo to give the acid chloride as a pale yellow solid.

To a solution of the crude acid chloride (˜0.52 mmol) in 3 mL of drymethylene chloride cooled in an ice-bath was added 180 μL (1.3 mmol,distilled from calcium hydride) of triethylamine followed by 83 μL (0.62mmol, Aldrich) of 3,3-dimethylbutylamine. The reaction mixture wasstirred for 15 minutes. The resulting solution was partitioned between20 mL lM aqueous HCl solution and 20 mL of ethyl acetate. The organiclayer was separated, dried (magnesium sulfate) and concentrated in vacuoto give an oil. The crude material was purified by flash chromatography(Merck silica, 12×1.5 cm, 2:1 ethyl acetate/hexane) to afford 205 mg(0.44 mmol, 84%) of title ester as a white solid, mp 156°-158°.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[(3,3-Dimethylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid

A mixture of 195 mg (0.42 mmol) of Part A ester and 70 mg (1.7 mmol,Aldrich) of lithium hydroxide monohydrate in 6 mL of 2:1 THF/water wasstirred rapidly at room temperature for 3 hours then acidified byaddition of 3.0 mL of lM HCl solution. The resulting solution waspartitioned between 20 mL of water and 20 mL of ethyl acetate. Theorganic layer was separated, dried (magnesium sulfate) and thenconcentrated in vacuo to give a solid. The crude material wasrecrystallized (ethyl acetate/hexane) to afford 155 mg (0.34 mmol, 81%)of title compound as white crystals, mp 160°-162°.

IR(KBr): 3427, 2956, 1716, 1653, 1605, 1524, 1208 cm⁻¹.

MS(CI): 455 (M+H)⁺.

OR: [α]_(D) =+27° (c=0.5 in chloroform)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.49, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Anal. Calc'd for C₂₆ H₃₄ N₂ O₅ :

C, 68.70; H, 7.54; N, 6.16;

Found: C, 68.70; H, 7.37; N, 6.23.

EXAMPLE 124 [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[[₂-(4-Fluorophenyl)-ethyl]amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-[2.2.1hept-₂ -yl]methyl]benzenepropanoic acid

A. [S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[₂-(4-Fluorophenyl)ethyl]amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-methyl]benzenepropanoic acid,methyl ester

To a solution of 200 mg (0.519 mmol) of oxazole acid prepared asdescribed in Example 2, Part J in 10 mL dry CH₂ Cl₂ (distilled from P₂O₅) was added 1 small drop of DMF, followed by 310 μL (0.62 mmol, ₂ M/CHCL₂, Aldrich) of oxalyl chloride solution. The reaction was stirred atroom temperature until gas evolution ceased (about 30 minutes), then themixture was concentrated in vacuo to give the crude acid chloride as apale yellow solid.

To a solution of crude acid chloride in 10 mL dry CH₂ Cl₂ (distilledfrom P₂ O₅), cooled to 0°, was added 170 μL (1.3 mmol, distilled fromCaH₂) of triethylamine, followed by the dropwise addition of 109 mg(0.62 mmol, Aldrich) of 4-fluorophenethylamine hydrochloride. Thereaction was stirred at 0° for 16 hours then partitioned between 80 mLethyl acetate/80 mL 1M HCl. The ethyl acetate layer was separated; thewater layer was extracted with two-30 mL portions of ethyl acetate. Thecombined ethyl acetate layers were dried (MgSO₄) and concentrated invacuo to give a crude yellow solid. The crude solid was flashchromatographed (Merck silica, 1:1 ethyl acetate/hexane) to give 108 mg(0.21 mmol, 41%) of title ester as a white solid, mp 199°-200°.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[₂-(4-Fluorophenyl)ethyl]amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-benzenepropanoic acid

To a solution of 108 mg (0.21 mmol) of Part A ester in 8 mL distilledTHF/2 mL water was added 18 mg (0.42 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 2 hours at roomtemperature, then quenched by the addition of 0.9 mL (0.9 mmol) lM HCl.The mixture was partitioned between 50 mL ethyl acetate/50 mL water; thewater layer was separated and extracted with two-25 mL portions of ethylacetate. The combined ethyl acetate layers were dried (MgSO₄) andconcentrated in vacuo to give a crude white solid. The crude solid wasrecrystallized from hot ethyl acetate/hexane to give 94 mg (0.19 mmol,86%) of title acid as a white solid, mp 187°-189°.

IR (KBr): 3443, 3425, 3109, 2954, 1713, 1645, 1605 cm⁻¹.

MS(CI): 493 (M+H)⁺.

OR: [α]_(D) =-0.9° (c=0.25 in MeOH)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.60, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Anal. Calc'd for C₂₈ H₂₉ N₂ O₅ F:

C, 68.28; H, 5.93; N, 5.69; F, 3.86;

Found: C, 68.12; H, 5.98; N, 5.80; F, 3.82.

EXAMPLE 125[1S(1α,2α,3α,4α)]-2-[[3-[4-[[(2-Phenylethyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid

A.[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-Phenylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid

To a solution of 200 mg (0.519 mmol) of acid prepared in Example 2, PartJ in 10 mL dry CH₂ Cl₂ (distilled from P₂ O₅) was added 1 small drop ofDMF, followed by 310 μL (0,62 mmol, 2M/CH₂ Cl₂, Aldrich) of oxalylchloride solution. The reaction was stirred at room temperature untilgas evolution ceased (about 30 minutes), then the mixture wasconcentrated in vacuo to give the crude acid chloride as a pale yellowsolid.

To a solution of crude acid chloride in 10 mL dry C₂ Cl₂ (distilled fromP₂ O₅), cooled to 0°, was added 120 μL (0.83 mmol, distilled from CaH₂)of triethylamine, followed by the dropwise addition of 80 μL (0.62 mmol,Matheson Co.) of phenethylamine. The reaction was stirred at 0° for 16hours, then partitioned between 80 mL ethyl acetate/80 mL lM HCl. Theethyl acetate layer was separated; the water layer was extracted withtwo-30 mL portions of ethyl acetate. The combined ethyl acetate layerswere dried (MgSO₄) and concentrated in vacuo to give a crude yellowsolid. The crude solid was flash chromatographed (Merck silica, 1:1ethyl acetate/hexane) to give 229 mg (0.47 mmol, 90%) of title ester asa white solid, mp 173°-175°.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(2-Phenylethyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -ylmethyl]benzene-propanoic acid

To a solution of 227 mg (0.464 mmol) of Part A ester in 8 mL distilledTHF/2 mL water was added 39 mg (0.93 mmol, Aldrich) of lithium hydroxidemonohydrate. The reaction was stirred vigorously for 1.5 hours at roomtemperature, then quenched by the addition of 1.9 mL (1.9 mmol) 1M HCl.The mixture was partitioned between 50 mL ethyl acetate/50 mL water; thewater layer was separated and extracted with two-25 mL portions of ethylacetate. The combined ethyl acetate layers were dried (MgSO₄) andconcentrated in vacuo to give a crude white solid. The crude solid wasrecrystallized from hot ethyl acetate to give 180 mg (0.38 mmol, 82%) oftitle acid as a white solid, mp 181°-183°.

IR (KBr): 3412, 3104, 2979, 2952, 1712, 1698, 1656, 1601 cm⁻¹.

MS(CI): 475 (M+H)⁺.

OR: [α]_(D) =+1.5° (c=0.5 in MeOH)

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.58, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Anal. Calc'd for C₂₈ H₃₀ N₂ O₅ :

C, 70.86; H, 6.37; N, 5.90;

Found: C, 70.43; H, 6.39; N, 5.84

EXAMPLE 126 1S-(1α,2α,3α,4α)]-₂-[[3-[4-[(6-Heptynylamino]-carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-₂-yl]methyl]benzenepropanoic acid

A. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[(6-Heptynylamino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid,methyl ester

To a stirred mixture of oxazole acid prepared in Example 2, Part J (151mg, 0.39 mmol) in 10 mL of dry CH₂ Cl₂ under argon at 0° C. was addedone drop of DMF and then added dropwise 1M solution of oxalyl chloridein CH₂ Cl₂ (0.47 mL, 0.47 mmol). The mixture was stirred at 0° C. for 30minutes and stirred at room temperature for 30 minutes. The mixture wasconcentrated in vacuo and dissolved in 10 mL of dry CH₂ Cl₂. The mixturewas concentrated in vacuo again and then redissolved in 8 mL of CH Cl₂.To this mixture at 0° C. under argon was added a solution oftriethylamine (Et₃ N) (0.16 mL, 1.18 mmol) and 6-heptynylaminehydrochloride salt (69.0 mg, 0.47 mmol) in 3 mL of CH₂ Cl₂. The mixturewas stirred at room temperature for 4 hours. The mixture was dilutedwith 200 mL of EtOAc and washed with 1NHCl solution (2×60 mL) andsaturated NaHCO₃ solution (1×60 mL). The organic layer was dried(MgSO₄), filtered and concentrated in vacuo. This was chromatographed on30 g of Merck silica gel 60 using ₂ % CH₃ OH/CH₂ Cl₂ as eluant to give154 mg (82%) of title ester.

TLC: silica gel, 6% CH₃ OH/CH₂ Cl₂, R_(f) 0.70, Ce(SO₄)₂.

¹³ C NMR of title compound (67.5 MHz, CDCl₃): δ 173.0, 163.7, 160.5,140.5, 138.4, 137.7, 136.1, 129.6, 128.9, 126.6, 126.4, 84.2, 79.6,78.6, 68.4, 51.5, 50.0, 46.9, 38.8, 34.8, 32.3, 29.8, 29.0, 28.8, 27.9,27.5, 25.9, 18.2.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[(6-Heptynylamino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-[2.2.1]hept-₂ -yl]methyl]-benzenepropanoic acid

To a stirred mixture of Part A ester (150 mg, 0.31 mmol) in 6 mL offreshly distilled THF was added 1.5 mL of water and LiOH monohydrate(39.5 mg, 0.94 mmol). The mixture was stirred at room temperature for 19hours and acidified to pH 2 by the addition of 1NHCl solution. Themixture was diluted with 10 mL of water, saturated with KCl andextracted with EtOAc (4×30 mL). The EtOAc extracts were dried (MgSO₄),filtered and concentrated in vacuo. Recrystallization in 4 mL ofacetonitrile at -5° C. gave 78 mg (54%) of title acid, m.p. 143°-144° C.

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.28, Ce(SO₄)₂.

¹³ C NMR of title compound (67.5 MHz, CDCl₃) δ 176.5, 163.9, 160.8,141.0, 138.5, 137.7, 135.8, 129.7, 128.9, 126.6, 126.4, 84.3, 79.6,78.6, 68.4, 49.9, 46.9, 38.9, 34.8, 32.4, 29.8, 28.9, 28.8, 27.9, 27.4,25.9, 18.2.

EXAMPLE 127 1S-(1α,2α,3α,4α)]-₂-[[3-[4-[[(4-Cyclohexylbutyl)-oxy]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept--yl]methyl]benzenepropanoic acid

A. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(4-Cyclo-hexylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -ylmethyl]benzene-propanoic acid,benzyl ester

To a mixture of 200 mg (0.39 mol) of Example 1 acid and 80 mg (0.58mmol, Mallinckrodt) of anhydrous granular potassium carbonate in 4 mL ofsieve-dried dimethylformamide (DMF) (Burdick and Jackson) was added 60μL (0.50 mmol, Aldrich) of benzyl bromide at room temperature. Thereaction was stirred for 3 hours, then partitioned between 25 mL ofwater and 25 mL of ethyl acetate. The organic layer was separated,washed with three-25 mL portions of water, dried (magnesium sulfate) andconcentrated in vacuo to give a solid. The crude solid wasrecrystallized (ethyl acetate/ hexane) to afford 198 mg (0.33 mmol, 85%)of title benzyl ester as a white solid, mp 114°-116°.

B. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[(4-Cyclo-hexylbutyl)oxy]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid,benzyl ester

A mixture of 190 mg (0.32 mmol) of Part A benzyl ester in 5 mL of 1:4glacial acetic acid/ acetic anhydride was warmed until homogeneous thencooled in an ice-bath. To the resulting solution was added in oneportion 480 mg (6.96 mmol, Mallinckrodt) of sodium nitrite. The reactionwas stirred for 45 minutes during which time a precipitate formed. Themixture was warmed to room temperature, an additional 480 mg (6.96 mmol)of sodium nitrite was added and stirring continued for 2.5 hours. Theresulting mixture was diluted with 25 mL of ethyl acetate then added to50 mL of water. The organic layer was separated, washed with two-50 mLportions of ice-cold lM aqueous NaOH solution, 20 mL of brine, dried(magnesium sulfate) and concentrated in vacuo to afford the crudeN-nitrosoamide as a yellow oil.

A solution of the crude N-nitrosoamide in 3 mL of dioxane (Burdick andJackson) was heated to 95° for 2 hours then cooled to room temperature.The solution color changed from yellow to colorless during this time.The resulting solution was concentrated in vacuo to give an oil. Thecrude oil was purified by flash chromatography (Merck silica, 12×3.0 cm,1:2 ethyl acetate/hexane) to afford 105 mg (0.18 mmol, 56%) of titlediester as a colorless glass.

C. [1S-(1α,2α,3α,4α)]-₂ -[[3-[4-[[(4-Cyclo-hexylbutyl)oxy]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]methyl]benzene-propanoic acid

A mixture 100 mg (0.17 mmol) of Part B benzyl ester and 20 mg of 10%palladium on activated carbon catalyst (Aldrich) in 5 mL of reagentethyl acetate was stirred rapidly under an atmosphere of hydrogen(balloon) for 5 hours then passed through a 0.4 μM polycarbonatemembrane. The filtrate was concentrated in vacuo to give a solid. Thecrude solid was recrystallized (ethyl acetate/hexane) to afford 68 mg(0.13 mmol, 79%) of title acid as a white solid, mp 135°-137°.

IR(KBr): 3438, 2922, 1721, 1633, 1581, 1215, 1151, 1110 cm⁻¹.

MS(CI): 510 (M+H)⁺.

OR: [α]_(D) =+44° (c=0.27 in chloroform).

TLC: R_(f) (silica gel, 1:9 methanol/methylene chloride)=0.54, ammoniummolybdate/ceric sulfate and UV, homogeneous.

Anal. Calc'd for C₃₀ H₃₉ NO₆ :

C, 70.70; H, 7.71; N, 2.75;

Found: C, 70.79; H, 7.79; N, 2.70

EXAMPLE 1A [1S-[1α,₂o(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)-amino]carbonyl]-.sub.2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid

A. [(1,1-Dimethylethoxy)carbonyl]-N-(4-cyclohexylbutyl)-L-serinamide

To a solution of5575 mg of 4-cyclohexylbutyl amine hydrochloride (3.0mmol), 615 mg t-butyloxy carbonyl-L-serine (3.0 mmol, 1.0 equiv), 405 mg1-hydroxybenzotriazole hydrate (3.0 mmol, 1.0 equiv), and 387 mgdiisopropylethylamine (3.0 mmol, 1.0 equiv) in 10 mL dry tetrahydrofuran(THF) stirring under argon at 0°, was added 618 mg1,3-dicyclohexylcarbodiimide (3.0 mmol, 1.0 equiv) in a single portion.A precipitate slowly formed. After 1 hour the mixture was warmed to roomtemperature and stirred for 4 hours. After dilution with ethyl acetate,the mixture was filtered, and the filtrate was washed with a pH 1 saltsolution (formed by mixing water, brine, and 1 M aqueous HCl solution).Further washing (twice) with 1 M NaHCO₃ was followed by drying over Na₂SO₄ and evaporation to give 1.1 g of crude title amide.

    ______________________________________                                        TLC (10% [10% conc. aqueous NH.sub.3 in CH.sub.3 OH] in                       CH.sub.2 Cl.sub.2 - anisaldehyde):                                            ______________________________________                                        cyclohexylbutylamine HCl                                                                          0.27                                                      title amide         0.47                                                      ______________________________________                                    

B. N-(4-Cyclohexylbutyl)-L-serinamide

To a solution of 1.1 g crude Part A amide in 4 mL CH₂ Cl₂ at roomtemperature was added 4 mL trifluoroacetic acid. The mixture was stirredfor 4 hours. After solvent evaporation, residual trifluoroacetic acidwas azeotropically removed by rotoevaporation with CHCl₃. Flashchromatography (150 g silica, 10% [10% concentrated aqueous NH₃ in CH₃OH] in CH₂ Cl₂) gave, after azeotroping with toluene and exposure tohigh vacuum, 495 mg of pure title amine as a white solid. The yield oftitle amine was 68% overall from 4-cyclohexylbutyl amine hydrochloride.

    ______________________________________                                        TLC (10% [10% conc. aqueous NH.sub.3 in CH.sub.3 OH] in CH.sub.2 Cl.sub.2     anisaldehyde):                                                                ______________________________________                                               Part A amide                                                                           0.47                                                                 title amine                                                                            0.17                                                          ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 173.4, 64.6, 56.3, 39.1, 37.3, 36.9, 33.1,29.6, 26.5, 26.2, 24.0

C. 1S-[1α,2α(Z),3α,4α]]-6-[3-(Hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-₂-yl]-4-hexenoic acid, methyl ester

To a partial solution of 36.27 g of4aR-(4aα,5β,8β,8aβ)]-octahydro-5,8-epoxy-1H-₂ -benzopyran-3-ol (preparedas described in U.S. Pat. No. 4,143,054) (0.23 mol) and3-carboxypropyl-triphenylphosphonium bromide (127.34 g, 0.37 mol) in 600mL of dry THF under argon at 3° C. was added dropwise over 1 hour asolution of 370.6 mL of potassium t-amylate (0.68 mol of a 1.8M toluenesolution) with mechanical stirring. Initially the reaction temperaturereached a maximum of 8° C. and subsequently leveled off to 4° C. for theremainder of the base addition. The reaction was then run at roomtemperature for 90 minutes. A 0° C. ice bath was introduced and thereaction was quenched by the addition of 152 mL of glacial acetic acid,over 30 minutes. Solvents were removed in vacuo (azeotroped withtoluene). Water (640 mL) and 50 mL of concentrated HCl were added (pH2.6). Dilution with 640 mL of ethyl acetate, the addition of 149 g ofNaCl and a few seed crystals of 3-carboxypropyltriphenylphosphoniumbromide was followed by vigorous stirring for 15 minutes. Theprecipitate was collected by filtration and washed with 2 portions eachof 320 mL of ethyl acetate. The ethyl acetate layer was separated, theaqueous layer was extracted with ethyl acetate (2×200 mL each), thecombined ethyl acetate layers were dried over MgSO and concentrated.Aqueous 5% K₂ CO₃ was added (507 mL) followed by vigorous stirring for 1hour. No precipitation occurred. The reaction mixture was concentratedto a paste and suspended in 508 mL of water. Several hours of vigorousstirring produced no precipitate. The water was decanted off and theresidue was suspended in 200 mL of aqueous 5% K₂ CO₃ solution. Aftervigorous stirring, a light tan solid was collected by filtration andrinsed several times with water. The combined aqueous layers wereextracted 5×with 1:1 toluene/ether (230 mL each). After cooling thecombined aqueous layers with a 0° C. ice bath, concentrated HCl wasadded to pH 2.5, followed by extraction 1 ×with 460 mL then 2×with 230mL each of ethyl acetate. The combined ethyl acetate layers were driedover MgSO₄ and evaporated in vacuo to yield 49.74 of an amber oil.Trituration from 330 mL of ether (room temperature, overnight) oiled outphosphorous by-products. The ether solution was decanted away from thedark red oil into a separatory funnel, and the oil which was carriedover by the decantation was drained off (1.56 g). Evaporation of theether solution in vacuo yielded 43.08 g of[1S-[1α,2α(Z),3α,4α]]-6-[3-hydroxymethyl)-7-oxabicyclo[2.2.1]hept-₂-yl]-4-hexenoic acid in the form of a viscous yellow oil.

¹ H NMR indicated a product: triphenylphosphine oxide: ether molar ratioof 23:1:1.8 (mass % 93:4.7:2.2). Yield exclusive of triphenylphosphineoxide/ether, 40.06 g (72.5%).

Acetyl chloride (5.20 mL, 0.073 mol) was added dropwise to 80 mL ofmethanol at room temperature under argon. The acetyl chloride/ methanolsolution was then added to a solution of 42.98 g (0.18 mol) in 700 mL ofmethanol in one portion. Stirring was continued for 3 hours.Triethylamine was added (0.09 mol, 12.21 mL), methanol was removed invacuo, and the residue was partitioned between 300 mL of ethyl acetateand 150 mL of water. After separation of the layers, the aqueous layerwas extracted with 150 mL of ethyl acetate, the combined ethyl acetatelayers were washed with brine, dried over Na₂ SO₄ and evaporated invacuo to yield 43.06 g of a viscous tan oil. Flash chromatography on1350 g of E. Merck Kieselgel 60 silica gel (240-400 mesh, 75/25ether/hexanes, then ether after the desired product began eluting offthe column) yielded 35.74 g title ester in the form of a viscous lightyellow oil, free from triphenylphosphine oxide by NMR.

¹ H NMR (CDCl₃, ref. TMS): δ 5.41-5.38, m (2H); 4.49, d, J=4.69Hz (1H);4.22, d, J=4.69Hz (1H); 3.73-3.69, m (1H); 3.67, s, (3H); 3.60, m (1H);2.37, br s (4H); 2.12-1.99m (3H); 1.97-1.85, m (1H); 1.72, m (2H); 1.46,m (2H).

¹³ C NMR (CDCl₃, ref. 77.00): δ 173.50, 130.42, 128.63, 80.23, 79.22,61.74, 51.49, 48.95, 46.45, 33.86, 29.69, 29.31, 25.94, 22.92

D. [1S-[1α,2α(Z),3α,4α]]-6-[3-(Carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 2.43 g of impure Part C alcohol (80% pure=1.94 g, 7.6mmol, contaminated with triphenylphosphine oxide) in 40 mL acetone underargon at 0°, was added slowly 8 mL Jones' Reagent (2.6 M in Cr^(VI)).The red color of the reagent persisted toward the end of the addition.This resulting precipitated mixture was stirred for 20 minutes before2-propanol was added to quench excess reagent. Still at 0°, 3 M aqueousNaHSO₃ solution was added with stirring until all salts dissolved. Brinewas added, and extraction (3 times) with ethyl acetate followed. Afterdrying the extracts over Na₂ SO₄ and solvent evaporation, flashchromatography (1450 g silica, 25% to 40% [5% acetic acid in ethylacetate] in hexane gradient) afforded, after azeotropic removal ofacetic acid with toluene, 1.91 g of an oil. This oil was impure titleacid (80% pure=1.53 g, contaminated with triphenylphosphine oxide),obtained in 75% yield.

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in                                 hexane - anisaldehyde):                                                       ______________________________________                                               Part C alcohol                                                                          0.33                                                                title acid                                                                              0.35                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 175.3, 173.1, 129.1, 128.8, 78.0, 78.0,51.6, 51.1, 47.4, 33.5, 28.8, 28.5, 26.9, 22.5

E.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 733 mg impure Part D acid (80% pure=586 mg, 2.2 mmol,1.1 equiv, contaminated with triphenylphosphine oxide) in 4 mL drytetrahydrofuran (THF) under argon was added 356 mg1,1'-carbonyldiimidazole (2.2 mmol, 1.1 equiv), and the mixture was leftfor 1 hour. Since a large volume of precipitate had formed, 5 mL dry THFwas added, and the mixture was gently warmed to obtain a solution. (TLCshowed a stable acylimidazole.) After stirring 30 minutes, a solution of495 mg Part B amine (2.0 mmol) in 10 mL dry THF was added using anadditional 5 mL THF to quantitatively transfer the amine. TLC of thehomogeneous mixture after 1 hour stirring at room temperature indicatedvery slow reaction. Therefore, THF was evaporated by passing argon overthe mixture overnight until its volume was reduced to 2 mL and aprecipitate had formed. Addition of 5 mL THF redissolved allprecipitate. After 5 hours more stirring, the mixture was evaporated,and flash chromatography (150 g silica, 50% to 100% ethyl acetate inhexane gradient, then 0% to 10% CH₃ OH in ethyl acetate gradient) gave230 mg of pure title hydroxybisamide as an oil. The yield of titlehydroxybisamide was 23%.

Also isolated were the isomeric aminoesteramide (27%) and the 2:1 adduct(16%). These by-products could be converted in good yields to titlehydroxybisamide by transesterification with KCN in CH₃ OH at roomtemperature, although the aminoesteramide may isomerize spontaneously.

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in                                 hexane - anisaldehyde):                                                       ______________________________________                                        Part B amine       0.00                                                       Part D acid        0.38                                                       acylimidazole      0.18                                                       title hydroxybisamide                                                                            0.22                                                       aminoesteramide    0.04                                                       2:1 adduct         0.33                                                       ______________________________________                                    

⁻⁻ C NMR (67.8 MHz in CDCl₃): 173.3, 172.8, 170.4, 129.2, 129.0, 78.9,78.8, 62.7, 54.0, 53.8, 51.3, 47.9, 39.4, 37.3, 36.9, 33.6, 33.1, 29.5,29.4, 28.6, 27.2, 26.4, 26.1, 24.0, 22.6

F.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

This chemistry is described by M. J. Miller, P. G. Mattingly, M. A.Morrison, and J. F. Kerwin, Jr., J. Am. Chem. Soc., 1980, 102, 7026.

To a solution of 240 mg of pure Part E hydroxybisamide (0.48 mmol) in 3mL dry THF under argon at room temperature, was added 189 mgtriphenylphosphine (0.72 mmol, 1.5 equiv), 73 mg triethylamine (0.72mmol, 1.5 equiv), and 89 mg CCl₄ (0.58 mmol, 1.2 equiv), and the mixturewas heated to reflux. After 1 hour another aliquot each of CCl₄ andtriethylamine were added, and after 2.5 hours more another aliquot ofeach were added again. 2 hours lateranother aliquot each of CCl₄ andtriethylamine and half an aliquot (95 mg) of triphenylphosphine wereadded. After 2 hours more, TLC finally indicated complete consumption ofPart E hydroxybisamide, and the initially colorless, homogeneous mixturehad formed a white precipitate and had darkened. Solvent evaporation wasfollowed by flash chromatography (silica, 15% acetone in toluene) whichafforded 190 mg of pure title oxazoline, an oil. The oxazoline wasobtained in 83% yield.

    ______________________________________                                        TLC (20% acetone in toluene - anisaldehyde):                                  ______________________________________                                        Part E hydroxybisamide                                                                            0.07                                                      title oxazoline     0.29                                                      ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 173.1, 171.2, 169.1, 129.3, 128.9, 79.0,78.9, 69.6, 68.3, 51.3, 48.2, 46.3, 39.0, 37.4, 36.9, 33.7, 33.1, 29.6,29.5, 28.7, 27.1, 26.5, 26.2, 24.0, 22.7

G. [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-4-hexenoic acid, methyl ester

This chemistry is described by D. L. Evans, D. K. Minster, U. Jordis, S.M. Hecht, A. L. Mazzu, Jr., and A. I. Meyers, J. Org. Chem., 1979, 44,497.

To a solution of 190 mg of pure Part F oxazoline (0.40 mmol) in 10 mLCHCl₃, was added 200 mg untitrated NiO₂, and the heterogenous mixturewas stirred at room temperature. TLC indicated some progress in thefirst 1 hour, but then reaction stopped. Over 1 day, five additionalaliquots of the reagent were added until the reaction was complete. Themixture was diluted with ethyl acetate, and this was stirred with 3 Maqueous NaHSO₃ solution until the black color of the NiO₂ disappearedand most of the solids dissolved. Extraction (3 times) with ethylacetate was followed by drying over Na₂ SO₄ and evaporation. Flashchromatography (silica, 25% to 35% ethyl acetate in hexane gradient)afforded 90 mg of pure title oxazole, a solid. The oxazole was obtainedin 48% yield.

    ______________________________________                                        TLC (100% ethyl acetate - anisaldehyde):                                      ______________________________________                                               Part F oxazoline                                                                         0.52                                                               title oxazole                                                                            0.81                                                        ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 173.2, 163.8, 160.5, 140.4, 136.0, 129.4,128.5, 79.5, 79.3, 51.4, 49.6, 46.6, 39.0, 37.4, 37.0, 33.7, 33.3, 29.8,29.7, 28.9, 27.8, 26.6, 26.3, 24.1, 22.7

H. [1S-1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-₂-oxazolyl]-7-oxabicyclo[2.2.1]hept-₂ -yl]-4-hexenoic acid

To 90 mg of pure Part G oxazole (0.19 mmol) in 4 mL CH₃ OH at roomtemperature, was added 2 mL of 1.0 M aqueous NaOH solution. Afterstirring the mixture for 1.3 hours, 1 M aqueous HCl solution was addedto lower the pH to 1. Extraction with ethyl acetate (3 times) followed.The extracts were dried over Na₂ SO₄, and solvent evaporation gave crudetitle acid. Flash chromatography (25% to 50% [5% acetic acid in ethylacetate] in hexane gradient) afforded, after azeotropic removal ofacetic acid with toluene, 71 mg of pure title acid as a solid. The yieldof title acid was 81%.

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in hexane -                        anisaldehyde):                                                                ______________________________________                                               Part G oxazole                                                                          0.43                                                                title acid                                                                              0.25                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 176.9, 163.9, 160.7, 140.9, 135.7, 129.5,128.4, 79.5, 79.3, 49.6, 46.5, 39.1, 37.4, 36.9, 33.7, 33.2, 29.7, 29.7,28.8, 27.8, 26.6, 26.2, 24.1, 22.5

EXAMPLE 2A1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)-methylamino]carbonyl]-₂-oxazolyl]-7-oxabicyclo-2.2.1]hept-₂ -yl]-4-hexenoic acid

A. N-[(1,1-(Dimethylethoxy)carbonyl]-O-(phenylmethyl)-L-serine, ₂-(trimethyl-silyl)ethyl ester

This chemistry is described by P. Sieber, Helv Chim. Acta, (1977), 60,2711.

To a solution of 20.7 g of N-t-butyloxy-carbonyl-O-benzyl-(L)-serine,(70 mmol), 11.0 g pyridine (139 mmol, 2.0 equiv), and 9.9 g2-trimethylsilylethanol (84 mmol, 1.2 equiv) in 50 mL dry CH₃ CNstirring under argon at 0°, was added 15.8 g1,3-dicyclohexylcarbodiimide (76 mmol, 1.1 equiv) in a single portion. Aprecipitate formed. After 3 hours the mixture was warmed to roomtemperature and stirred for 12 hours. A solution of 1.4 g oxalic aciddihydrate (11 mmol, 0.15 equiv) in 3 mL dimethylformamide (DMF) wasadded, and the mixture was stirred for 1 hour before filtration. Thefiltercake was washed with ethyl acetate until the filtrate was free oftitle ester. The filtrate was washed twice with 1M aqueous HCl solutionplus brine and twice with 1M aqueous NaHCO₃ solution. Drying over Na₂SO₄ and evaporation gave 34.8 g of crude title ester (79% pure=27.6 g,contaminated with solvent and 2-trimethylsilylethanol) as an oil in 100%yield.

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in                                 hexane - anisaldehyde):                                                       ______________________________________                                        N-BOC-O-benzyl-(L)-serine                                                                          0.40                                                     Part A ester         0.84                                                     ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 170.5, 155.3, 137.5, 128.2, 127.6, 127.4,79.5, 73.0, 69.9, 63.6, 54.0, 28.1, 17.2, -1.7

B. N-[(1,1-Dimethylethoxy)carbonyl]-L-serine, 2-(trimethylsilyl)ethylester

To a solution of 34.8 g of crude Part A ester (79% pure =27.6 g,contaminated with solvent and ₂ -trimethylsilylethanol, 70 mmol) in 200mL ethyl acetate plus 300 mL acetic acid at room temperature under argonwas added 10 g of 10% Pd on carbon catalyst. The mixture was thenstirred under an atmosphere of H₂ for 4 days. TLC showed nearly completeclean conversion. The mixture was filtered through a polycarbonatemembrane, and after evaporation of the solvent, residual acetic acid wasremoved by azeotroping with toluene and CH₂ Cl₂. Flash chromatography(750 g silica, 10% to 30% ethyl acetate acid in hexane gradient) gave3.58 g of pure starting material, Part A ester, (13% yield) and 16.49 gof pure title debenzylated ester as an oil. The yield of title ester was78%.

    ______________________________________                                        TLC (25% ethyl acetate in hexane - anisaldehyde):                             ______________________________________                                               Part A ester                                                                           0.61                                                                 Part B ester                                                                           0.28                                                          ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 170.9, 155.6, 79.9, 63.8, 63.0, 55.8, 28.1,17.2, -1.7

C. L-serine, ₂ -(Trimethylsilyl)ethyl ester, monohydrochloride

This chemistry is described by P. Sieber, R. H. Andreatta, K. Eisler, B.Kamber, B. Riniker, and H. Rink, Peptides: Proceedings of the FifthAmerican Peptide Symposium, M. Goodman and J. Meienhofer, Eds., HalstedPress, New York. (1977), pp. 543-545.

To a solution of 10.4 g of Part B ester (34.1 mmol) in 200 mL diethylether was added 40 mL of an approximately 6.5 M HCl/methanol/methylacetate solution (260 mmol). (This solution was prepared by adding 42 gacetyl chloride (0.54 mmol) dropwise to 35 g methanol (1.1 mmol)stirring at 0° followed by stirring at room temperature for 2 hours).The mixture was then stirred for 4 hours during which gas slowlyevolved. While stirring in a room temperature bath, 32.8 g NaHCO₃ (390mmol) was added cautiously in small portions to control gas evolutionduring neutralization. The mixture was then filtered through a glassfrit, using 50% methanol in diethyl ether to wash the filtercake.Evaporation of the solvent gave 8.06 g of the semisolid, crude, nearlypure title amine hydrochloride. This material may have been only apartial salt, but assuming a pure 1:1 salt the yield was 98%.

    ______________________________________                                        TLC (10% [10% concentrated aqueous NH.sub.3 in CH.sub.3 OH] in                CH.sub.2 Cl.sub.2 -anisaldehyde):                                             ______________________________________                                               Part B ester                                                                           0.63                                                                 Part C amine                                                                           0.22                                                          ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): 171.3, 63.9, 61.9, 55.5, 17.1, -1.8

D.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[[[1-(Hydroxymethyl)-2-oxo-2-[(trimethylsilyl)ethoxy]ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 9.40 g, Example 1, Part D acid (85% pure=7.99 g, 29.8mmol), 8.04 g of crude, nearly pure Part C amine hydrochloride (95%pure=7.60 g, 31.6 mmol, 1.06 equiv), 4.43 g 1-hydroxybenzotriazolehydrate (32.8 mmol, 1.1 equiv), and 4.24 g diisopropylethylamine (32.8mmol, 1.1 equiv) in 50 mL dry THF stirring under argon at roomtemperature, was added approximately 6.8 g 1,3-dicyclohexylcarbodiimide(33 mmol, 1.1 equiv) in a single portion. A precipitate slowly formed.After 16 hours, the solvent was evaporated, and flash chromatography(silica, 30% to 100% ethyl acetate in hexane gradient) gave an oilcontaining a solid. This material was taken up in diethyl ether in whichthe solid did not dissolve, and filtered. Evaporation gave 9.45 g ofnearly pure title amide (90% pure=8.51 g), a clear oil. The yield oftitle amide was 63%.

    ______________________________________                                        TLC (10% [10% concentrated aqueous NH.sub.3 in CH.sub.3 OH]                   in CH.sub.2 Cl.sub.2 - anisaldehyde):                                         ______________________________________                                               Part C amine                                                                           0.37                                                                 Part D amide                                                                           0.65                                                          ______________________________________                                    

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in                                 hexane - anisaldehyde):                                                       ______________________________________                                        Example 1, Part D acid                                                                            0.42                                                      Part D amide        0.36                                                      ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 173.5, 172.4, 170.3, 129.4, 129.1, 79.2,79.1, 63.9, 63.2, 54.6, 54.5, 51.4, 47.8 33.7, 29.7, 28.5, 27.3, 22.7,17.2, -1.7

E.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[4,5-Dihydro-4-[[2-(trimethylsilyl)ethoxy]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 8.3 g of nearly pure Part D amide (90% pure=7.5 g, 16.6mmol) in 150 mL dry CH₃ CN under argon at room temperature (roomtemperature bath), was added 13.1 g triphenylphosphine (50 mmol, 3.0equiv), 6.4 g diisopropylethylamine (50 mmol, 3.0 equiv), and finally7.7 g CCl₄ (50 mmol, 3.0 equiv). After stirring for 2 hours, 1M aqueousNaHCO₃ solution was added, and the mixture was extracted three timeswith . CH₂ Cl₂. Drying over Na₂ SO₄ was followed by evaporation andflash chromatography (silica, 20% to 50% ethyl acetate in hexanegradient) which afforded 5.9 g of nearly pure title oxazoline (90%pure=5.3 g), an oil. The oxazoline was obtained in 73% yield.

    ______________________________________                                        TLC (50% ethyl acetate in hexane - anisaldehyde):                             ______________________________________                                        Part D amide     0.20                                                         Part E oxazoline 0.44                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃) 172.7, 170.7, 169.0, 129.0 128.8, 78.3,78.3, 69.0, 67.5, 63.2, 50.9, 48.1, 46.0, 33.4, 29.3, 28.4, 26.7, 22.4,16.8, -2.0

F.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[2-(Trimethylsilyl)ethoxy]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

This chemistry is described by D.L. Evans, D. K. Minster, U. Jordis, S.M. Hecht, A. L. Mazzu, Jr., and A.I. Meyers, J. Org. Chem., (1979), 44,497.

To a solution of 5.1 g of nearly pure Part E oxazoline (90% pure=4.6 g,10.5 mmol) in 50 mL CH₂ Cl₂, was added 10.1 g untitrated NiO₂, and theheterogenous mixture was stirred at room temperature. (Exothermicreaction resulted in the mixture warming somewhat.) TLC indicated nearlycomplete reaction after 1 hour. An additional aliquot, 2.0 g, of NiO₂was then added. After 30 minutes the reaction was complete, and 150 mLethyl acetate was added. To reduce and dissolve the Ni salts, 100 mL 3Maqueous NaHSO₃ solution and 200 mL 1M aqueous trisodium citrate solutionwere added. Stirring caused all of the solids to dissolve, and themixture warmed. Separation and extraction twice more with ethyl acetate(TLC indicated complete extraction of title oxazole) was followed bydrying over Na SO.sub. and evaporation. Flash chromatographicpurification of the 3.8 g of crude product (150 g silica, 20% to 75%ethyl acetate in hexane gradient) afforded 2.60 g of pure title oxazole,an oil. The oxazole was obtained in 57% yield.

    ______________________________________                                        TLC (50% ethyl acetate in hexane - anisaldehyde):                             ______________________________________                                               Part E oxazoline                                                                         0.34                                                               Part F oxazole                                                                           0.58                                                        ______________________________________                                    

¹³ C--NMR (67.8 MHz in CDCl₃) 172.9, 164.5, 161.0, 143.3, 133.0, 129.1,128.4, 79.0, 78.9, 63.0 51.1, 49.5, 46.8, 33.5, 29.5, 28.7, 27.6, 22.5,17.2, -1.8

G.[1S-[1α,2α(Z),3α,4α]]-6-[3-(4-Carboxy-2-oxazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

This chemistry is described by P. Sieber, R. H. Andreatta, K. Eisler, B.Kamber, B. Riniker, and H. Rink, Peptides: Proceedings of the FifthAmerican Peptide Symposium, M. Goodman and J. Meienhofer, Eds., HalstedPress, New York, (1977), pp.543-545.

To a solution of 3.1 g of pure Part F oxazole (7.1 mmol) in 20 mL dryDMF under argon, was added 12.0 g of tetrabutylammonium fluoride onsilica (Fluka, 13.9 mmol, 1.96 equiv), and the heterogenous mixture wasstirred at room temperature for 6 hours. The mixture was diluted with 20mL of 1% F₃ CCO₂ H, 1% CH₃ OH, 98% ethyl acetate and filtered using 40mL of the same solvent to wash the filtercake. The filtrate wasevaporated and azeotroped three times with toluene to remove the DMF.The crude product was purified on an ion exchange resin: After washing a250 g column of AG 50W-X8 (hydrogen form) with water and then 50% CH₃ OHin water until the eluant was colorless, the crude product dissolved in40 mL of 50% CH₃ OH in water was loaded, and elution was carried outwith the same solvent. This afforded 2.65 g of nearly pure title oxazoleacid (90% pure=2.38 g), an oil. The oxazole acid was obtained in 100%yield.

    ______________________________________                                        TLC (1% F.sub.3 CCO.sub.2 H, 1% CH.sub.3 OH, 98% ethyl acetate -              anisaldehyde):                                                                ______________________________________                                        Part F oxazole    0.46                                                        Part G oxazole acid                                                                             0.15                                                        ______________________________________                                    

hu 13C NMR (67.8 MHz in CD30D): 175.0, 166.7, 163.8, 45.6, 134.2, 130.4,129.7, 80.7, 80.7, 52.0, 50.7, 7.7, 34.6, 30.5, 29.7, 28.9, 23.8

H. N-Methyl-4-cyclohexylbutylamine, monohydrochloride

To a solution of 750 mg of 4-cyclohexylbutylamine hydrochloride (3.9mmol) and 1.08 g triethylamine (10.8 mmol, 2.8 equiv) in 10 mL dry THFstirring under argon at 0°, was added 584 mg ClCO₂ C₂ H₅ (5.4 mmol, 1.4equiv). After warming to room temperature, the heterogeneous mixture wasstirred for 3 hours. Dilution with diethyl ether was followed by washing(twice) with 1M aqueous HCl solution. The organic layer was dried overNa₂ SO₄ and evaporated to obtain 950 mg of crude ethyl carbamateintermediate, an oil, contaminated with some of the imide.

To a solution of 950 mg of crude ethyl carbamate intermediate in 10 mLdry THF stirring under argon at 0°, was added 950 mg lithium aluminumhydride (25 mmol, 6.4 equiv). Gas was evolved. The mixture was thenheated to reflux for 2 hours. After recooling to 0° and adding 20 mLdiethyl ether, 1.0 mL water was cautiously added to quench excesshydride. The mixture was rewarmed to room temperature, and whilestirring vigorously, 1.0 mL 15% aqueous NaOH solution, then 3.0 mL waterwere added. The mixture was filtered, washing the filter cake with 10%[10% concentrated aqueous NH in CH₃ OH] in diethyl ether, and thefiltrate was evaporated. This material was evaporated several times withCH₃ OH to remove NH3, and finally acidified with concentrated aqueousHCl solution. Azeotropic removal of water with toluene and CH₃ OHyielded, after exposure to high vacuum, 830 mg of impure secondary aminehydrochloride (80% pure=660 mg, contaminated with tertiary aminehydrochloride) as a solid. The product was obtained in 83% yield and wastaken on without purification.

    ______________________________________                                        TLC (10% [10% concentrated aqueous NH.sub.3 in CH.sub.3 OH]                   in CH.sub.2 Cl.sub.2 -anisaldehyde):                                          ______________________________________                                        4-cyclohexylbutylamine                                                                            0.07                                                      carbamate intermediate                                                                            0.89                                                      Part H amine        0.11                                                      ______________________________________                                    

I.[1S-1α,2α(Z),3a,4α]]-6-[3-[4-[(4-Cyclohexylbutyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A sample of impure Part G oxazole acid (contaminated withtetrabutylammonium, but as the free acid, 0.20 mmol) was dried byazeotroping with dry DMF and toluene twice (high vacuum). This materialwas placed in 2 mL toluene, and while stirring the heterogeneous mixtureat room temperature under argon, 127 mg oxalyl chloride (1.0 mmol, 5equiv) was added. Gas was evolved. After 1 hour an additional 127 mgoxalyl chloride was added. Again gas was evolved. This mixture wasstirred overnight. TLC indicated clean conversion to the acid chloridehaving the name[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-(chlorocarbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester. The solvent was evaporated, and toluene was addedand evaporated again to purge any remaining oxalyl chloride.

To the crude acid chloride of the Part G acid was added 4 mL CHCl₃. Thematerial did not all dissolve. While stirring under argon at roomtemperature, 100 mg of impure Part H secondary amine hydrochloride (80%pure=80 mg, contaminated with tertiary amine hydrochloride, 0.39 mmol, 2equiv) and 145 mg triethylamine (1.4 mmol, 7 equiv) were added. Afterstirring at room temperature for 1 hour, the mixture was diluted withethyl acetate, water was added, and extraction (twice) with ethylacetate was followed by drying over Na and evaporation. This gave 120 mgof impure title amide as a gum. The crude product was taken on withoutpurification.

    ______________________________________                                        TLC (1% F.sub.3 CCO.sub.2 H, 1% CH.sub.3 OH, 98% ethyl acetate -              anisaldehyde):                                                                ______________________________________                                        Part G oxazole acid 0.28                                                      acid chloride intermediate                                                                        0.78                                                      Part I amide        0.64                                                      ______________________________________                                    

J.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To 120 mg of impure Part I amide in 6 mL CH₃ OH at room temperature, wasadded 2 mL of 1.0M aqueous NaOH solution. After stirring the mixture for3 hours, 1M aqueous HCl solution was added to lower the pH to 1.Extraction with ethyl acetate (3 times) followed. The extracts weredried over Na₂ SO₄, and solvent evaporation gave crude acid titleproduct. Flash chromatography (50% to 100% [5% acetic acid in ethylacetate] in hexane gradient) afforded, after azeotropic removal ofacetic acid with toluene, 70 mg of pure title product as an oil. Theyield of title product was 72% overall from the impure Part G oxazoleacid.

    ______________________________________                                        TLC (50% [5% acetic acid in ethyl acetate] in                                 hexane - anisaldehyde):                                                       ______________________________________                                        Part I amide      0.36                                                        Part J Title Product                                                                            0.20                                                        ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃. Two conformations were seen. Lines clearlydue to only one conformation are listed in parentheses.): 177.0, 163.1,(162.3), (162.0), 142.5, 136.4, 129.6, 128.5, 79.5,79.4, (50.4), 49.7,(48.7), 46.7, 37.5, 37.0, (36.4), 34.1, 33.3, 29.7, 29.0, 27.9, (27.2),26.6, 26.3, (24.2), (23.7), 22.9

EXAMPLE 3A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(1-Pyrrolidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A. 1-[N-[(1,1-Dimethylethoxy)carbonyl]-L-seryl]ovrrolidine

To a stirred solution of pyrrolidine (1.11 g, 15.7 mmol),t-butyloxycarbonyl (BOC)-(L)-serine (3.22 g, 15.7 mmol),1-hydroxybenzotriazole hydrate (2.12 g, 15.7 mmol) and diisopropylethylamine (2.73 mL, 15.7 mmol) in 30 mL of THF under argon was added1,3-dicyclohexylcarbodiimide (3.23 g, 15.7 mmol). This mixture wasstirred at room temperature for 17 hours and concentrated in vacuo. Themixture was diluted with 200 mL ethyl acetate and the precipitate wasfiltered off. The precipitate was rinsed with ethyl acetate (3×40 mL).The combined filtrates were washed with 1N aqueous HCl solution (3×70mL), and saturated NaHCO₃ solution (2×80 mL). The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo. This waschromatographed on 140 g of Merck silica gel 60 using 2% CH₃ OH in CH₂Cl₂ as eluant to give 1.64 g (41%) of title amide.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.24, Ce(SO₄)₂

¹³ C NMR (67.5 MHz, CDCl ) δ: 169.4, 155.6, 79.7, 62.8, 53.5, 46.5,45.9, 28.0, 28.0 28.0, 25.7, 23.8

B.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[[[1-(Hydroxymethyl)-2-oxo-2-(1-pyrrolidinyl)ethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part A amide (0.96 g, 3.72 mmol) in 20 mL ofdry CH₂ Cl₂ under argon at 0° C. was added 5 mL of trifluoroacetic acid(TFA). The mixture was stirred at 0° C. for 2 hours and diluted with 50mL of toluene. This mixture was concentrated in vacuo. To a stirredsolution of this amine-TFA salt, 1-hydroxybenzotriazole hydrate (0.50 g,3.73 mmol), and 5 mL of triethylamine in 20 mL of DMF was added asolution of Example 1, Part D acid (1.00 g, 3.73 mmol) in 10 mL of DMF.To this mixture was then added ethyl-3(3-dimethylamino)propylcarbodiimide hydrochloride salt. The reaction mixture was stirred atroom temperature for 19 hours and concentrated in vacuo. The mixture wasdiluted with 400 mL of ethyl acetate and washed with 1N HCl solution(3×30 mL), 0.2N NaOH solution (2×30 mL) and brine (1×60 mL). The organiclayer was dried (MgSO₄), filtered, and concentrated in vacuo.Purification was effected by flash chromatography on 50 g of Mercksilica gel 60 using 0.4 L each of 2% and 4% CH₃ OH in CH₂ Cl₂ as eluantsto give 320 mg (22%) of title alcohol.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.22, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 174.4, 172,2, 168.8, 129.3, 129.2, 78.9,78.9, 63.5, 54.3, 52.2, 51.4, 48.0, 46.6, 45.9, 33.7, 29.5, 28.8, 27.2,25.8, 24.0, 22.7

C.1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[4,5-Dihydro-4-[(1-pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part B alcohol (305 mg, 0.75 mmol) anddiisopropylethyl amine (0.39 mL, 2.24 mmol) in 10 mL of CH₂ Cl₂ underargon at 0° C. was added methanesulfonyl chloride (0.07 mL, 0.90 mmol).This mixture was stirred at room temperature for 4 hours andconcentrated in vacuo. The crude mesylate was dissolved in 30 mL ofacetone and combined with 0.60 g of K₂ CO₃. This mixture was heated toreflux for 4 hours, cooled to room temperature, and diluted with 100 mLof acetone. The precipitate was filtered off and rinsed with acetone(3×40 mL). The filtrate was concentrated in vacuo and chromatographed on50 g of Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give210 mg (72%) of title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.20, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.4, 168.2, 167.7, 129.5, 129.1, 78.9,78.9, 68.7, 67.5, 51.4, 48.4, 46.5, 46.4, 46.1, 33.9, 29.7, 28.8, 27.1,25.9, 24.1, 22.8

D.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-(1-Pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part C oxazoline (200 mg, 0.51 mmol) in 5 mL ofCH₂ Cl₂ was added mg of NiO₂. The reaction mixture was stirred at roomtemperature for 3 hours at which time another 200 mg of NiO₂ was added.The mixture was stirred at room temperature for 1 hour and 200 mg ofNiO₂ was added. This mixture was stirred for another 1 hour and one moreportion of 200 mg of NiO₂ was added. The reaction mixture was stirred atroom temperature for 17 hours and diluted with 80 mL of ethyl acetate.To the resulting mixture was added 5 mL of 3M NaHSO₃ solution and 40 mLof 1M sodium citrate solution. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (3×70 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and concentrated invacuo. This was chromatographed on 18 g of Merck silica gel 60 using 2%CH₃ OH in CH₂ Cl₂ as eluant to give 69.2 mg (35%) of title ester.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.24, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.2, 163.1, 160.3, 142.2, 137.1, 129.3,128.7, 79.4, 79.1, 51.4, 49.6, 48.2, 46.7, 46.6, 33.7, 29.7, 28.9, 27.8,26.4, 23.7, 22.7

E.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(1-Pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid

To a stirred solution of Part D ester (69.0 mg, 0.18 mmol) and 2 mL ofwater in 12 mL of THF was added 2 mL of 1N LiOH solution. This mixturewas sparged with argon for 10 minutes and stirred at room temperaturefor 7 hours. The mixture was acidified to pH 2 by the addition of 1N HClsolution and saturated with NaCl. The THF layer was separated and theaqueous layer was extracted with ethyl acetate (4×60 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 10 g of Mercksilica gel 60 using 10% CH₃ OH in CH₂ Cl₂ as eluant to give 26 mg (39%)of title acid.

TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.22, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, DMSO-d ) δ: 175.1, 163,2, 159.6, 142.2, 136.3,130.5, 127.6, 78.8, 78.4, 48.8, 47.7, 46.3, 45.8, 29.3, 28.4, 27.5,25.9, 23.3, 23.2, 22.8

EXAMPLE 4A[1S-[1α,2α(Z),3α,4α]]-6-3-[4-[(Cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A. [(1,1-Dimethylethoxy)carbonyl]-N-cyclohexvl-L-serinamide

To a stirred solution of cyclohexylamine (1.11 g, 15.7 mmol),Boc-(L)-serine (3.22 g, 15.7 mmol), 1-hydroxybenzotriazole hydrate (2.12g, 15.7 mmol) and diisopropylethyl amine (2.73 mL, 15.7 mmol) in 30 mLof THF under argon at 0° C. was added 1,3-dicyclohexylcarbodiimide (3.23g, 15.7 mmol). This mixture was stirred at room temperature for 18hours. The mixture was diluted with 200 mL ethyl acetate and theprecipitate was filtered. The precipitate was rinsed with ethyl acetate(3×40 40 mL). The combined filtrates were washed with 1N aqueous HClsolution (3×70 mL), and saturated NaHCO₃ solution (2×80 mL). The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo. This waschromatographed on 140 g of Merck silica gel 60 using 2% CH₃ OH in CH₂Cl₂ as eluant to give 1.64 g (41%) of title amide.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.24, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 170.1, 156.1, 80.2, 62.7, 48.1, 32.6,32.6, 28.1, 28.1, 28.1, 25.3, 24.5, 24.5, 24.5

B.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[[[2-(Cyclohexylamino)-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part A amide (1.06 g, 3.73 mmol) in 20 mL ofdry CH₂ Cl₂ under argon at 0° C. was added 5 mL of TFA. The mixture wasstirred at 0° C. for 2 hours and diluted with 50 mL of toluene. Thismixture was concentrated in vacuo. To a stirred solution of thisamine-TFA salt, 1- hydroxybenzotriazole hydrate (0.50 g, 3.73 mmol), and6 mL of triethyl amine in 20 mL of DMF was added a solution of ExamplelA, Part D acid (1.00 g, 3.73 mmol) in 10 mL of DMF. To this mixture wasthen added ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloridesalt (0.55 g, 3.73 mmol). The reaction mixture was stirred at roomtemperature for 19.5 hours and concentrated in vacuo. The mixture wasdiluted with 400 mL of ethyl acetate and washed with 1N HCl solution(3×40 mL), 0.2N NaOH solution (2×30 mL), saturated NaHCO₃ solution (1×30mL) and brine (1×100 mL). The organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. Purification was effected by flashchromatography on 60 g of Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂as eluant to give 690 mg (42%) of title alcohol.

TLC: Silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.30, Ce(SO₄)₂

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.3, 173.0, 169.6, 129.4, 129.0, 79.1,78.9, 62.7, 54.4, 53.7, 51.4, 48.2, 48.0, 33.7, 32.6, 32.6, 32.6, 29.5,28.6, 27.5, 25.3, 24.6, 24.6, 22.7

C.[1S-[1α,2α(Z),3α(R*),4α]-6-[3-[4-[(Cyclohexylamino)carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part B alcohol (680 mg, 1.56 mmol) anddiisopropylethyl amine (0.82 mL, 4.68 mmol) in 20 mL of CH₂ Cl₂ underargon at 0° C. was added methanesulfonyl chloride (0.13 mL, 1.63 mmol).This mixture was stirred at room temperature for 1 hour and concentratedin vacuo. The crude mesylate was dissolved in 20 mL of acetone andcombined with 647 mg of K₂ CO₃ This mixture was heated at 54° C. for 3.5hours, cooled to room temperature and diluted with 100 mL of acetone.The precipitate was filtered off and rinsed with acetone (3×50 mL). Thefiltrate was concentrated in vacuo and chromatographed on 50 g of Mercksilica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 540 mg (83%)of title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.42, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.2, 170.4, 169.2, 129.5, 128.9, 79.1,79.0, 69.7, 68.4, 51.4, 48.4, 47.8, 46.4, 33.8, 33.0, 32.8, 29.6, 28.9,27.3, 25.4, 24.7, 24.7, 22.8

D.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(Cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoicacid, methyl ester

To a stirred solution of Part C oxazoline (530 mg, 1.26 mmol) in 5 mL ofCH₂ Cl₂ was added 1.06 g of NiO₂. The reaction mixture was stirred atroom temperature for 3 hours at which time another 530 mg of NiO₂ wasadded. The mixture was stirred at room temperature for 1 hour and 530 mgof NiO₂ was added. This mixture was stirred for another 80 minutes anddiluted with 120 mL of ethyl acetate. To the resulting mixture was added10 mL of 3M NaHSO₃ solution and 70 mL of 1M sodium citrate solution. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate (2×100 mL). the combined organic extracts were washed withbrine (1×100 mL), dried (MgSO₄), filtered, and concentrated in vacuo.This was chromatographed on 40 g of Merck silica gel 60 using 2% CH₃ OHin CH₂ Cl₂ as eluant to give 370 mg (70%) of title ester.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.64, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.2, 163.7, 159.6, 140.6, 136.1, 129.4,128.5, 79.5, 79.3, 51.4, 49.6, 47.8, 46.6, 33.7, 33.0, 33.0, 29.7, 28.8,27.8, 25.4, 24.9, 24.9, 22.7

E.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(Cyclohexylamino)carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a stirred solution of Part D ester (360 mg, 0.86 mmol) and 10 mL ofwater in 60 mL of THF was added 10 mL of 1N LiOH solution. This mixturewas sparged with argon for 10 minutes and stirred at room temperaturefor 7 hours. The mixture was acidified to pH 2 by the addition of 1N HClsolution and saturated with NaCl. The THF layer was separated and theaqueous layer was extracted with ethyl acetate (4×80 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 40 g of Mercksilica gel 60 using 4% CH₃ OH in CH₂ Cl₂ as eluant to give 300 mg (86%)of title acid.

TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.32, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 176.9, 163.9, 160.0, 141.0, 129.5, 128.5,79.5, 79.5, 48.1, 46.6, 33.7, 32.9, 32.9, 29.7, 28.9, 27.9, 25.5, 24.9,24.9

EXAMPLE 5A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A. [(1,1-Dimethylethoxy)carbonyl]-N-(2-cyclohexylethyl)-L-serinamide

To a stirred solution of 2-cyclohexylethylamine (2.00 g, 15.7 mmol),Boc-(L)-serine (3.22 g, 15.7 mmol), 1-hydroxybenzotriazole hydrate (2.12g, 15.7 mmol) and diisopropylethyl amine (2.73 mL, 15.7 mmol) in 40 mLof THF under argon at 0° C. was added 1,3-dicyclohexylcarbodiimide (3.23g, 15.7 mmol). This mixture was stirred at room temperature and 10 mL ofDMF was added. The reaction mixture was then stirred at room temperaturefor 18 hours. The mixture was diluted with 300 mL ethyl acetate and theprecipitate was filtered. The precipitate was rinsed with ethyl acetate(3×40 mL). The combined filtrate was washed with 1N aqueous HCl solution(3×70 mL), and saturated NaHCO₃ solution (2×80 mL). The organic layerwas dried (MgSO₄), filtered and concentrated in vacuo. This waschromatographed on 160 g of Merck silica gel 60 using 1:4 hexanediethylether as eluant to give 1.91 g (39%) of title amide.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.34, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 171.1, 80.3, 62.9, 37.3, 36.8, 35.2, 33.1,33.1, 28.3, 28.3, 28.3, 26.4, 26.1, 26.1[1S-1α,2α(Z),3α(R*),4a]]-6-[3-[[2-[(2-Cyclohexylethyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part A amide (1.28 g, 3.73 mmol) in 20 mL ofdry CH₂ Cl₂ under argon at 0° C. was added 5 mL of TFA. The mixture wasstirred at 0° C. for 2 hours and diluted with 50 mL of toluene. Thismixture was concentrated in vacuo. To a stirred solution of thisamine-TFA salt, 1-hydroxybenzotriazole hydrate (0.50 g, 3.73 mmol), and5 mL of triethylamine in 20 mL of DMF was added a solution of Example 1,Part D acid (1.00 g, 3.73 mmol) in 10 mL of DMF. To this mixture wasthen added ethyl-3(3-dimethylamino)propyl carbodiimide hydrochloridesalt (0.55 g, 3.73 mmol). The reaction mixture was stirred at roomtemperature for 17 hours and concentrated in vacuo. The mixture wasdiluted with 400 mL of ethyl acetate and washed with 1N HCl solution(3×40 mL), 0.2N NaOH solution (2×30 mL), saturated NaHCO₃ solution (1×30mL) and brine (1×100 mL). The organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. Purification was effected by flashchromatography on 60 g of Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂as eluant to give 1.00 g (54%) of title alcohol.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.30, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.4, 172.9, 170.4, 129.3, 129.0, 79.0,78.9, 62.7, 54.2, 53.7, 51.4, 48.0, 37.3, 36.6, 35.3, 33.7, 32.9, 32.9,29.5, 28.6, 27.3, 26.3, 26.0, 26.0, 22.7

C.[1S-1α,2α(Z),3α(R*),4α]]-6-[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part B alcohol (890 mg, 1.80 mmol) anddiisopropylethyl amine (0.94 mL, 5.40 mmol) in 30 mL of CH₂ Cl₂ underargon at 0° C. was added methanesulfonyl chloride (0.14 mL, 1.80 mmol).This mixture was stirred at room temperature for 1 hour and concentratedin vacuo. The crude mesylate was dissolved in 30 mL of acetone andcombined with 0.77 g of K₂ CO₃. This mixture was heated to reflux for 4hours, cooled to room temperature, and diluted with 100 mL of acetone.The precipitate was filtered off and rinsed with acetone (3×50 mL). Thefiltrate was concentrated in vacuo and chromatographed on 60 g of Mercksilica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 480 mg (54%)of title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.42, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.1, 171.2, 169.2, 129.4, 128.9, 79.1,79.0, 69.6, 68.3, 51.4, 48.3, 46.3, 36.9, 36.8, 35.2, 33.7, 33.0, 32.9,29.6, 28.8, 27.2, 26.3, 26.1, 26.1, 22.8

D.[1S-[1α,2α(Z),3a,4a]]-6-[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part C oxazoline (480 mg, 1.01 mmol) in 20 mLof CH₂ Cl₂ was added 480 mg of NiO₂. The reaction mixture was stirred atroom temperature for 1 hour at which time another 480 mg of NiO₂ wasadded. The mixture was stirred at room temperature for 3 hours and 480mg of NiO₂ was added. This mixture was stirred for another 15.5 hoursand one more portion of 480 mg of NiO₂ was added. The reaction mixturewas stirred for 1.5 hours and diluted with 100 mL of ethyl acetate. Tothe resulting mixture was added 20 mL of 3M NaHSO₃ solution and 30 mL of1M sodium citrate solution. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with brine (1×50 mL), dried (MgSO₄),filtered, and concentrated in vacuo. This was chromatographed on 45 g ofMerck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 200 mg(42%) of title ester.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.60, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.1, 163.7, 160.4, 140.3, 136.0, 129.3,128.4, 79.4, 79.3, 51.3, 49.6, 46.6, 36.9, 36.7, 35.2, 33.6, 33.0, 33.0,29.7, 28.8, 27.7, 26.4, 26.0, 26.0, 22.7

E.1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(2-Cyclohexylethyl)amino]carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a stirred solution of Part D ester (190 mg, 0.40 mmol) and 4 mL ofwater in 30 mL of THF was added 4 mL of 1N LiOH solution. This mixturewas sparged with argon for 10 minutes and stirred at room temperaturefor 5 hours. The mixture was acidified to pH 2 by the addition of 1N HClsolution and saturated with NaCl. The THF layer was separated and theaqueous layer was extracted with ethyl acetate (4×25 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 20 g of Mercksilica gel 60 using 4% CH₃ OH in CH₂ Cl₂ as eluant to give 106.7 mg(59%) of title acid.

TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.32, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 176.9, 163,9, 160.7, 140.8, 135.7, 129.4,128.4, 79.5, 79.4, 49.6, 46.5, 36.9, 36.8, 35.2, 33.7, 33.0, 33.0, 29.6,28.8, 27.8, 26.4, 26.1, 26.1, 22.6

EXAMPLE 6A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A. [(1,1-Dimethylethoxy)carbonyl]-N[2-(4-chlorophenyl)ethyl]-L-serinamide

To a stirred solution of 2-(4-chlorophenyl)ethylamine (2.44 g, 15.7mmol), Boc-(L)-serine (3.22 g, 15.7 mmol), 1-hydroxybenzotriazolehydrate (2.12 g, 15.7 mmol) and diisopropylethyl amine (2.73 mL, 15.7mmol) in 30 mL of THF under argon at 0° C. was added1,3-dicyclohexylcarbodiimide (3.23 g, 15.7 mmol). This mixture wasstirred at room temperature and 10 mL of DMF was added. The reactionmixture was then stirred at room temperature for 18 hours. The mixturewas diluted with 200 mL ethyl acetate and the precipitate was filtered.The precipitate was rinsed with ethyl acetate (3×40 mL). The combinedfiltrates was washed with 1N aqueous HCl solution (3×70 mL), andsaturated NaHCO solution (2×80 mL). The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. This was chromatographed on 160 g ofMerck silica gel 60 using 1:4 hexanediethyl ether as eluant to give 2.56g (48%) of title amide.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.34, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.1, 157.6, 139.2, 133.1, 131.4, 131.4,129.4, 129.4, 80.8, 63.3, 58.0, 41.7, 35.7, 34.7, 28.7, 28.7, 28.7

B.[1S-[1a,2a(Z),3α(R*),4a]]-6-[3-[[[2-[[2-(4-Chlorophenyl)ethyl]amino]-1-(hydroxymethyl)-2-oxoethylamino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part A amide (1.28 g, 3.73 mmol) in 20 mL ofdry CH₂ Cl₂ under argon at 0° C. was added 5 mL of TFA. The mixture wasstirred at 0° C. for 2 hours and diluted with 50 mL of toluene. Thismixture was concentrated in vacuo. To a stirred solution of thisamine-TFA salt, 1-hydroxybenzotriazole hydrate (0.50 g, 3.73 mmol), and5 mL of triethylamine in 20 mL of DMF was added a solution of Example 1,Part D acid (1.00 g, 3.73 mmol) in 10 mL of DMF. To this mixture wasthen added ethyl-3(3-dimethylamino)propyl carbodiimide hydrochloridesalt (0.55 g, 3.73 mmol). The reaction mixture was stirred at roomtemperature for 17 hours and concentrated in vacuo. The mixture wasdiluted with 400 mL of ethyl acetate and washed with 1N HCl solution(3×40 mL), 0.2N NaOH solution (2×30 mL), saturated NaHCO solution (1×30mL) and brine (1×100 mL). The organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. Purification was effected by flashchromatography on 60 g of Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂as eluant to give 1.00 g (54%) of title alcohol.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.30, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.5, 172.9, 170.6, 137.2, 132.1, 130.0,130.0, 129.3, 129.1, 128.5, 128.5, 79.0, 78.9, 62.7, 54.1, 53.9, 51.4,48.0, 40.8, 34.8, 33.7, 29.5, 28.7, 27.3, 22.7

C.[1S-[1α,2α(Z),3e(R*),4α]]-6-[3-[4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part B alcohol (890 mg, 1.80 mmol) anddiisopropylethyl amine (0.94 mL, 5.40 mmol) in 30 mL of CH₂ Cl₂ underargon at 0° C. was added methanesulfonyl chloride (0.14 mL, 1.80 mmol).This mixture was stirred at room temperature for 1 hour and concentratedin vacuo. The crude mesylate was dissolved in 30 mL of acetone andcombined with 0.77 g of K₂ CO₃ This mixture was heated to reflux for 4hours, cooled to room temperature, and diluted with 100 mL of acetone.The precipitate was filtered off and rinsed with acetone (3×50 mL). Thefiltrate was concentrated in vacuo and chromatographed on 60 g of Mercksilica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 480 mg (54%)of title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.42, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 171.6, 169.4, 169.3, 137.0, 132.3, 130.0,130.0, 129.5, 129.0, 128.6, 128.6, 79.1, 79.0, 69.6, 68.3, 51.5, 48.2,46.3, 40.0, 34.8, 33.8, 29.6, 28.9, 27.2, 22.8

D.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part C oxazoline (480 mg, 1.01 mmol) in 20 mLof CH₂ Cl₂ was added 480 mg of NiO₂. The reaction mixture was stirred atroom temperature for 1 hour at which time another 480 mg of NiO₂ wasadded. The mixture was stirred at room temperature for 3 hours and 480mg of NiO₂ was added. This mixture was stirred for another 15.5 hoursand one more portion of 480 mg of NiO₂ was added. The reaction mixturewas stirred for 1:5 hours and diluted with 100 mL of ethyl acetate. Tothe resulting mixture was added 20 mL of 3M NaHSO₃ solution and 30 mL of1M sodium citrate solution. The organic layer was separated and theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were washed with brine (1×50 mL), dried (MgSO₄),filtered, and concentrated in vacuo. This was chromatographed on 45 g ofMerck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 200 mg(42%) of title ester.

TLC: silica gel, 4% C₃ OH in CH₂ Cl₂, R_(f) 0.60, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 173.2, 163.9, 160.6, 140.5, 137.2, 135.8,132.2, 130.0, 130.0, 129.4, 128.6, 128.6, 128.5, 79.5, 79.3, 51.4, 49.6,46.6, 40.1 35.2, 33.7, 29.7, 28.9, 27.8, 22.7

E.[1S-[1α,2α(Z),3a,4α]]-6-[3-4-[[[2-(4-Chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a stirred solution of Part D ester (190 mg, 0.40 mmol) and 4 mL ofwater in 30 mL of THF was added 4 mL of 1N LiOH solution. This mixturewas sparged with argon for 10 minutes and stirred at room temperaturefor 5 hours. The mixture was acidified to pH 2 by the addition of 1N HClsolution and saturated with NaCl. The THF layer was separated and theaqueous layer was extracted with ethyl acetate (4×25 mL). The combinedorganic extracts was dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 20 g of Mercksilica gel 60 using 4% CH₃ OH in CH₂ Cl₂ as eluant to give 106.7 mg(59%) of title acid.

TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.32, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl₃) δ: 176.9, 175.4, 164.0, 160.9, 140.9, 137.2,130.1, 130.1, 129.4, 128.6, 128.6, 79.6, 79.5, 49.6, 46.6, 40.2, 35.1,33.7, 29.7, 28.9, 27.9, 22.6

EXAMPLE 7A[1S-[1α,2α(Z),3%,4a]-6-[3-[4-[[(4-Chlorophenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-4-hexenoicacid

A. [(1,1-Dimethylethoxy)carbonyl]-N-(4-chlorophenyl)-L-serinamide

To a stirred solution of 4-chloroaniline (2.00 g, 15.7 mmol),Boc-(L)-serine (3.22 g, 15.7 mmol), 1-hydroxybenzotriazole hydrate (2.12g, 15.7 mmol) and diisopropylethyl amine (5.40 mL, 31.2 mmol) in 40 mLof DMF under argon was added ethyl-3(3-dimethylamino)propylcarbodiimide, hydrochloride salt (2.31 g, 15.7 mmol). This mixture wasstirred at room temperature for 17 hours and concentrated in vacuo. Themixture was diluted with 400 mL ethyl acetate and washed with 1N aqueousHCl solution (3×70 mL), and saturated NaHCO₃ solution (2×70 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was chromatographed on 80 g of Merck silica gel 60 using 1 L ofeach of 1:3 and 1:4 hexane-diethyl ether as eluants to give 1.02 g (21%)of title amide.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.34, Ce(SO₄)₂.

B.[1S-[1α,2α(Z),3e(R*),4e]]-6-[3-[[[2-[(4-Chlorophenyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part A amide (1.02 g, 3.24 mmol) in 12 mL ofdry CH₂ Cl₂ under argon at 0° C. was added 3 mL of TFA. The mixture wasstirred at 0° C. for 3 hours and diluted with 50 mL of toluene. Thismixture was concentrated in vacuo. To a stirred solution of thisamine-TFA salt, 1-hydroxybenzotriazole hydrate (0.50 g, 3.73 mmol), and5 mL of triethylamine in 20 mL of DMF was added a solution of Example 1,Part D acid (1.00 g, 3.73 mmol) in 10 mL of DMF. To this mixture wasthen added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloridesalt. The reaction mixture was stirred at room temperature for 17 hoursand concentrated in vacuo. The mixture was diluted with 400 mL of ethylacetate and washed with 1N HCl solution (3×30 mL), 0.2N NaOH solution(2× 30 mL) and brine (1×100 mL). The organic layer was dried (MgSO₄),and concentrated in vacuo. Purification was effected by flashchromatography on 80 g of Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂as eluant to give 380 mg (22%) of title alcohol.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.31, Ce(SO₄)₂.

C.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[4-[[(4-Chlorophenyl)aminocarbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part B alcohol (370 mg, 0.80 mmol) anddiisopropylethyl amine (0.42 mL, 2.39 mmol) in 5 mL of CHCl under argonat 0° C. was added methanesulfonyl chloride (0.068 mL, 0.88 mmol). Thismixture was stirred at room temperature for 30 minutes and concentratedin vacuo. The crude mesylate was dissolved in 10 mL of acetone andcombined with 0.70 g of K CO₃. This mixture was heated almost to refluxfor 3 hours, cooled to room temperature and diluted with 100 mL ofacetone. The precipitate was filtered off and rinsed with acetone (3×30mL). The filtrate was concentrated in vacuo and chromatographed on 35 gof Merck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 210mg (59%) title oxazoline.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.68, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.2, 170.0, 169.6, 135.8, 129.5, 129.4,128.9, 128.9, 128.5, 120.9, 120.9, 79.2, 79.2, 69.4, 68.7, 51.4, 48.3,46.4, 33.7, 29.6, 28.8, 27.2, 22.8

D[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Chlorophenyl)aminocarbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of Part C oxazoline (200 mg, 0.45 mmol) in 3 mL ofCH₂ Cl₂ was added 200 mg of NiO₂. The reaction mixture was stirred atroom temperature for 1.5 hours at which time another 200 mg of NiO₂ wasadded. The mixture was stirred at room temperature for 1.5 hours and 200mg of NiO₂ was added. This mixture was stirred for another 1.5 hours andone more portion of 200 mg of NiO₂ was added. The reaction mixture wasstirred for 2 hours and diluted with 100 mL of ethyl acetate. To theresulting mixture was added 5 mL of 3M NaHSO₃ solution and 30 mL of 1Msodium citrate solution. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (2×100 mL). The combined organicextracts were dried (MgSO₄), filtered, and concentrated in vacuo. Thiswas chromatographed on 15 g of Merck silica gel 60 using 2% CH₃ OH inCH₂ Cl₂ as eluant to give 140 mg (70%) of title ester.

TLC: silica gel, 4% CH₃ OH in CH₂ Cl₂, R_(f) 0.76, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 173.2, 164.2, 158.4, 141.4, 136.0, 135.9,129.5, 129.3, 128.9, 128.9, 128.4, 121.1, 121.1, 79.6, 79.4, 51.4, 49.6,46.6, 33.7, 29.7, 28.9, 27.9, 22.8

E.[1S-[1α,2α(Z),3a,4α]]-6-[3-[4-[[(4-Chlorophenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a stirred solution of Part D ester (135 mg, 0.03 mmol) and 3 mL ofwater in 15 mL of THF was added 3 mL of 1N LiOH solution. This mixturewas sparged with argon for 10 minutes and stirred at room temperaturefor 5 hours. The mixture was acidified to pH 2 by the addition of 1N HCl. solution and saturated with NaCl. The THF layer was separated and theaqueous layer was extracted with ethyl acetate (4×15 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification was effected by flash chromatography on 15 g of Mercksilica gel 60 using 4% CH₃ OH in CH₂ Cl₂ as eluant to give 79.2 mg (61%)of title acid.

TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.36, Ce(SO₄)₂.

¹³ C NMR (67.5 MHz, CDCl ) δ: 179.0, 177.6, 164.2, 141.7, 136.0, 135.9,129.4, 128.9, 128.5, 121.2, 121.2, 79.7, 79.5, 49.6, 46.6, 33.6, 32.3,29.7, 28.9, 27.9, 22.6

EXAMPLE 8A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-vl]-4-hexenoicacid

A.1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1hept-2-yl]-4-hexenoicacid, methyl ester

0.21 g of impure Example 2A, Part G compound (50% pure=0.11 g, 0.33mmol) was stirred in about 4 mL toluene, and 0.1 mL (1.14 mmol) ofoxalyl chloride was added. One drop of dimethylformamide was added, andthe mixture was stirred for 2 hours at room temperature after which thereaction was complete by

TLC. The reaction mixture was concentrated in vacuo; the residue wasreconcentrated twice from 2 mL of toluene to afford an orange oil namely[1S-[1α,2α(Z),3α,4α]]-6-(4-(chlorocarbonyl)-2-oxazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester. To this oil was added about 3 mL of CHCl followed by0.11 mL (0.08 g, 0.78 mmol) of triethylamine and 0.13 g (0.71 mmol) of4-(4-chlorophenyl)butylamine, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetateand water, the organic layer was separated, and the aqueous layer wasextracted twice with 20 mL of ethyl acetate. The organic layers werecombined, washed with brine, dried over MgSO₄, and concentrated in vacuoto afford 0.43 g of an orange oil. This oil was flash chromatographed(silica; 0% to 100% ethyl acetate in hexane gradient) to obtain 0.26 gof impure title methyl ester (50% pure=0.13 g) as an oil. The productwas obtained in 78% yield.

¹³ C NMR (67.8 MHz, CDCl ) δ: 172.8, 163.6, 160.3, 140.2, 140.2, 135.7,131.0, 129.4, 129.1, 128.2, 128.0, 79.2, 79.1, 51.1, 49.4, 46.3, 38.4,34.4, 33.5, 29.4, 28.6, 28.1, 27.6, 22.5

B.[1S-[1α,2α(Z),3α,4e]]-6-[3-[4-[[[4-(4-Chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

0.26 g of impure Part A ester (50% pure=0.13 g, 0.26 mmol) was stirredin about 30 mL 1N NaOH and 2 mL of THF for 8 hours at room temperature.The reaction mixture was concentrated to remove THF and acidified to pHabout 2 with concentrated HCl. Ethyl acetate was added and the organiclayer was separated. The aqueous layer was extracted twice with about 20mL ethyl acetate. The organic layers were combined, washed withsaturated NaCl, dried over MgSO₄, and concentrated in vacuo to give 0.2g of a clear oil. This was flash chromatographed (silica, 0.50% CH₃ OH;0.25% CH₂ CO₂ H; 99.25% ethyl acetate) to provide 0.10 g of pureproduct. The product was obtained in 79% yield.

¹³ C NMR (67.8 MHz, CDCl ) δ: 178.4, 164.4, 161.4, 141.0, 140.4, 135.6,131.3, 129.6, 129.3, 128.5, 128.3, 79.5, 79.4, 49.6, 46.5, 38.8, 34.6,33.6, 29.6, 28.9, 28.4, 27.8, 22.5

EXAMPLE 9A[1S-[1α,2α(Z),3α,4α]]-6-[3[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-vl]-4-hexenoicacid

A.[1S-1α,2α(Z),3a,4α]]-6-[3-{Aminocarbonyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of Example lA, Part D acid (2.45 g, 9.13 mmol) in drybenzene (100 mL) was added, dropwise over a 10 minute period, oxalylchloride (0.96 mL, 11 mmol). After stirring for 5 hours, the reactionwas concentrated in vacuo, dissolved in dry THF (10 mL) and addeddropwise over a 5 minute period to a 0° C. solution of concentratedammonium hydroxide (3 mL) in THF (100 mL). The reaction was thenconcentrated in vacuo. The residual solid was partitioned between ethylacetate (150 mL) and 0.25M K₂ CO₃ (25 mL). The aqueous layer wasextracted with ethyl acetate (25 mL). The combined organic layers weredried (Na₂ SO₄) and concentrated in vacuo. The residue (2.2 g) wassuspended in boiling ether (100 mL). Ethyl acetate (ca. 10 ;%L) wasadded to effect solution. The mixture was concentrated to ca. 50 mL on asteam bath, cooled to room temperature, seeded and chilled overnight.Pure title amide (1.19 g, 49%) was obtained by filtration. Additionaltitle amide (145 mg) was obtained by concentration of the mothor liquorsto 15 mL and allowing crystallization to occur.

B.[1S-[1α,2α(Z),3α,4α]]-6-[3-(Aminothiocarbonyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a 60° C. solution of Part A amide (267 mg, 0.999 mmol) in dry toluene(10 mL) was added Lawesson's Reagent (222 mg, 0.55 mmol). The reactionwas stirred at 60° C. for 30 minutes, diluted with diethyl ether (50mL), and washed with half-saturated NaHCO₃ (2×5 mL). The organic layerwas dried (Na₂) and concentrated in vacuo. The residue was passedthrough a short silica plug using 50% ethyl acetate/hexanes to yield ayellow solid (249 mg, 88%).

C.[1S-[1α,2α(Z),3α,4α]-6-[3-(4-carboxy-2-thiazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of Part B thioamide (400 mg, 1.41 mmol) and powderedanhydrous K₂ CO₃ (390 mg, 2.82 mmol) in dry DMF (10 mL) was added, inseveral portions, bromopyruvic acid (contains 0.4 mol water/molbromoacid, 295 mg, 1.69 mmol). The reaction was allowed to stir at roomtemperature for 30 minutes. After this time, an additional 29.5 mgportion of bromopyruvic acid was added. After an additional 1 hour, thesolvent was removed in vacuo below 30° C. The residue wassuspended/dissolved in methylene chloride (10 mL). Triethylamine (0.59mL, 4.2 mmol) was added followed by the dropwise addition ofmethanesulfonyl chloride (0.33 mL, 4.2 mmol). After stirring for 5minutes, the reaction was diluted with diethyl ether (40 mL). Theorganic layer was extracted with 0.5M K₂ CO₃ (9×10 mL). The combinedaqueous layers were brought to pH 1.5 with 6N HCl and extracted withdiethyl ether (6×25 mL). These combined organic layers were dried(Na2SO₄) and concentrated in vacuo. The yield of the product acid was212 mg (43%).

D.[1S-[1α,2α(Z),3α,4a]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2yl]-4-hexenoicacid, methyl ester

To a solution of Part C acid (42.0 mg, 0.120 mmol) in dry DMF (1 mL) wasadded 1,1'-carbonyldiimidazole (20.3 mg, 0.125 mmol). The reaction wasallowed to stir for 1 hour. A solution of (cyclohexylbutyl)aminehydrochloride (23.4 mg, 0.131 mmol) and triethylamine (0.020 mL, 0.14mmol) in dry DMF (0.5 mL) was then added. The reaction was stirred for 1hour, and concentrated to remove DMF. The residue was taken up indiethyl ether (20 mL) and 0.5N HCl (5 mL). The organic layer was dried(Na ) and concentrated in vacuo. The resultant amide (46.8 mg, 81%) waschromatographed (silica, 50% ethyl acetate/hexanes) to yield 37.1 mg(64%) of title ester as a colorless oil.

E.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a solution of Part D amide in methanol (1 mL) was added 2N KOH (0.3mL). The reaction was stirred for 2 hours. After an additional 0.3 mLportion of KOH was added. After an additional 1 hour, the reaction wasconcentrated to remove methanol. The residue was dissolved in water (1mL) and 1N HCl was added to bring the pH to 2. The mixture was extractedwith methylene chloride (3×5 mL). the combined organic layers were dried(Na SO₄) and concentrated in vacuo to yield an oil (34.7 mg, 96%).

EXAMPLE 10A[1S-[1α,2α(Z),3α,4α]]-6-[3-[5-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A.2-(((1,1-Dimethylethoxy)carbonyl)amino)-3-(((phenylmethoxy)carbonyl)amino)propanoicacid

N-α-Boc-asparagine (18.0 g, 77.5 mmol) was added to a solution ofbis(trifluoroacetoxy)iodosylbenzene (50.0 g, 116.3 mmol) in 1/1 DMF/H₂ O(620 mL). After 15 minutes, pyridine (12.5 mL, 155.1 mmol) was added.The dark yellow solution was stirred overnight (16 hours). The now paleyellow solution was concentrated in vacuo below 40° C. The residue wasdiluted with water (600 mL), washed with diethyl ether (6×400 mL), andthen concentrated in vacuo. This crude product was dissolved in water(100 mL). To the solution was added 0.5M Na₂ CO₃ to bring the pH to ca.8. Then, THF (100 mL) was added. To this vigorously stirred mixture wasadded, dropwise benzylchloroformate (CBZ--Cl) (80% pure determined byNMR integration; 19.8 g, 93.0 mmol) dissolved in THF (50 mL). AdditionalNa₂ CO₃ solution was added as needed to maintain a basic pH (as judgedby pH 5- 10 range pH strips). One hour after the addition was completed,the reaction was concentrated to remove THF. The residue was extractedwith diethyl ether (3×200 mL). The aqueous layer was brought to pH 2with concentrated H The mixture was extracted with diethyl ether (4×200mL). These latter extracts were dried (Na₂ SO₄) and concentrated invacuo. Chromatography (80% ethyl acetate/hexanes containing 1% aceticacid) yielded 4.23 g (16%) of a slightly impure title product.

R_(f) (silica, ethyl acetate+0.5% acetic acid) 0.27.

B. 2-(Trimethylsilyl)ethyl2-(((1,1-dimethylethoxy)carbonyl)amino)-3-(((phenylmethoxy)carbonyl)amino)propanoate

To a 0° C. solution of the Part A acid (3.96 g, 11.7 mmol) in dry TIF(50 mL) was added 1,1'-carbonyldiimidazole (2.08 g, 12.9 mmol). After 1hour, 2-(trimethylsilyl)ethanol (3.4 mL) was added. The reaction wasthen brought to 70° C. for 1 hour. After cooling, the reaction .wasconcentrated and chromatographed (flash, silica, 50 mm dia, 25% ethylacetate/hexanes) to yield 3.08 g (60%) of title ester in the form atransparent oil: R_(f) (silica, 25% ethyl acetate/hexanes) 0.32.

C. 3-Amino-2-[[(1,1-dimethylethoxy)carbonyl]amino]propanoic acid,2-(trimethylsilyl)ethyl ester

To a solution of the Part B Z-amine (2.89 g, 6.60 mmol) in2-propanol/water (65 mL/6 mL) was added ammonium formate (2.08 g, 33.0mmol) and then a slurry of Pd/C (10%, 0.5 g) in 2-propanol (4 mL). Themixture was stirred at room temperature for 1 hour. The reaction wasfiltered through Celite® and concentrated in vacuo. The residue wastaken up in 70 mL of ethyl acetate and 30 mL of saturated NaClcontaining 8 mL of 5N NaOH. The aqueous layer was further extracted withethyl acetate (2×70 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo to give title compound in the form of anoil (1.85 g, 92%): R_(f) (silica, 10% methanol/chloroform) 0.75.

D.[1S-[1α,2α(Z),3α,4α]]-6-[3-[[[2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-oxo-3-[2-(trimethylsilyl)ethoxypropyl]amino]thioxomethyl]-7-oxabicyclo[2.2.1hept-2-yl]-4-hexenoicacid, methyl ester

WSC (1.18 g, 6.15 mmol) was added to a solution of[1S-[1α,2α(Z),3α,4α]]-6-[3-(carboxy)-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester (1.65 g, 6.15 mmol), Part C compound (1.85 g, 6.08mmol), and HOBT (831 mg, 6.15 mmol) in methylene chloride (60 mL). Thereaction was stirred for 16 hours, diluted with methylene chloride (300mL) extracted (1×50 mL of 1N HCl; 1×50 mL of saturated NaHCO_(3;) 1×50mL of water) dried (Na₂ SO₄) and concentrated in vacuo. Chromatography(flash, silica, 50 mm dia, 40% ethyl acetate/hexanes, 2L; 60% ethylacetate, lL) yielded an oil: 2.11 g (63%): R_(f) (silica, 10%methanol/chloroform) 0.67.

The preceding amide (1.94 g, 3.50 mmol) was stirred at 65° C. in benzene(40 mL) with Lawesson's Reagent (850 mg, 2.10 mol) for 1.5 hours. Thereaction was cooled and diluted with diethyl ether (250 mL). The mixturewas washed (2×50 mL of 0.5N Na₂ CO₃), dried (Na₂ SO₄), concentrated invacuo, and chromatographed (flash, silica, 50 mm dia, 25% ethylacetate/hexanes) to yield 1.61 g (80%) of title compound in the form ofan oil: R_(f) (silica, 25% ethyl acetate/hexanes) 0.14.

E.[1S-1α,2α(Z),3α,4α]]-6-3-[1-[(1,1-Dimethylethoxy)carbonyl]-4,5-dihydro-5-[[2-(trimethylsilyl)ethoxy]carbonyl-1H-imidazole-2-yl]-7-oxabicyclo[2.2.1hept-2-yl]-4-hexenoicacid, methyl ester

Carbon tetrachloride (3.00 mL, 31.2 mmol) was added to a solution ofPart D compound (1.61 g, 2.82 mmol), triphenylphosphine (2.22 g, 8.46mmol), triethylamine (1.18 mL, 8.46 mmol) in dry acetonitrile (28 mL).The reaction was stirred for 4 hours. The reaction was diluted withdiethyl ether (125 mL), saturated NaCl (125 mL) and water (5 mL). Theaqueous phase was further extracted with ether (125 mL). The combinedorganic layers were dried (Na₂ SO₄) and concentrated in vacuo. Theresidue was triturated sequentially with ether (20 mL, 10 mL and 7 mL),each time taking and concentrating the filtrate for the next cycle.Chromatography (flash, silica, 50 mm dia, 50% ethyl acetate/hexanes)yielded 1.09 g (72%) of title compound in the form of an oil: R_(f)(silica, 50% ethyl acetate/hexanes) 0.29.

F.1S-[1α,2(Z),3α,4α]]-6-[3-(5-Carboxy-4,5-dihydro-1H-imidazole-2-yl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester, monohydrochloride

To a solution of Part E compound (1.09 g, 2.03 mmol) in methylenechloride (2 mL) was added trifluoroacetic acid (4 mL). The reaction wasstirred at room temperature for 1 hour, diluted with toluene (40 mL) andwas then concentrated in vacuo. The residue was taken up in ethylacetate (60 mL) and was washed (2×5 mL) with saturated NaHCO₃. Theorganic layer was dried (Na and concentrated in vacuo to yield1S-(1α,2α(Z),3α,4α]]-6-[3-(5-carboxy-4,5-dihydro-1H-imidazol-2-yl)-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester (261 mg, 27%). The aqueous phase was brought to pH 2and concentrated in vacuo. Extraction of the solid with chloroform (2×15mL) followed by concentration in vacuo yielded title compound (553 mg,73%).

G.[1S-[1α,2α(Z),3α,4α]]-6-[3-[5-[[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A mixture of Part F acid (516 mg, 1.38 mmol), (4-cyclohexylbutyl)aminehydrochloride (345 mg, 1.80 mmol), WSC (345 mg, 1.80 mmol), HOBT (243mg, 1.80 mmol) and triethylamine (0.50 mL, 3.6 mmol) in methylenechloride (15 mL) was stirred for 24 hours. The reaction was diluted withmethylene chloride (50 mL) and was washed (2×10 mL of saturated NaHCO₃),dried (Na₂ SO₄) and concentrated in vacuo to yield a yellowish oil,namely[1S-[1α,2α(Z),3α,4α]]-6-[3-[5-[[(4-cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester. This oil was dissolved in chloroform (20 mL). ActiveMnO₂ (Aldrich, 1.0 g) was added. The reaction was stirred for 24 hours.An additional 0.5 g portion of MnO₂ was added and stirring was continuedfor 3 days. Further MnO (0.5 g) was added. After 5 hours, the reactionwas filtered through Celite®. The pad was rinsed with portions ofchloroform. The combined filtrates were concentrated in vacuo.Chromatography (flash, silica, 25 mm dia, 2% methanol/chloroform)yielded 235 mg (36%) of title ester compound in the form of an oil.

EXAMPLE 11A[1S-[1α,2α(Z),3α,4e]]-6-[3-4-[(4-Cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

To a solution of Example 10A ester in methanol (8 mL) was added 2N KOH(4 mL). The reaction was stirred at room temperature for 4 hours. Themethanol was removed in vacuo. The residue was taken up in methylenechloride (25 mL) and brought to pH 2 with 1N HCl. After shaking, theaqueous layer was further extracted with methylene chloride (25 mL). Thecombined organic layers were dried (Na₂ SO₄) and concentrated in vacuo.The residue was taken up in methylene chloride (10 mL) and swirled withethereal HCl (4 mL) for 30 seconds. The mixture was concentrated invacuo. Trituration with 10 mL of ethyl acetate (boiling to roomtemperature) yielded a white solid which was collected by filtration,washed with ethyl acetate (5 mL) and dried to yield title acid as awhite solid: 126.4 mg (52%); mp 168°-173° C.

¹ H NMR (tetradeuteriomethanol/deuteriochloroform, 270 MHz): δ 8.05 (s,1H), 5.23-5.36 (m, 2H), 4.73 (s, 1H), 4.41 (s, 1H), 3.74 (d, J=8 Hz,1H), 3.34-3.37 (m, 2H), 0.84-2.44 (m, 28H);

¹³ C NMR (complete decoupling, 67.8 MHz,tetradeuteriomethanol/deuteriochloroform): δ 175.4, 157.0, 147.8, 130.1,127.3, 120.7, 80.0, 79.9, 44.9, 39.8, 37.4, 36.9, 33.5, 33.1, 29.1,28.7, 28.1, 26.5, 26.2, 24.1, 22.6.

IR (KBr): 3427 (m), 3232 (m), 3009 (m), 2923 (s), 2851 (m), 1730 (m),1718 (m), 1651 (m), 1566 (m), 1448 (w), 1334 (w), 1189 (w) cm⁻¹.

LRMS (Cl, NH DEP 50, pos. ion spectrum) m/z (rel. int.) 458 (2), 184(7), 173 (14), 172 (6), 169 (9), 168 (13), 167 (5), 157 (10), 156 (100),155 (25), 154 (35), 152 (6).

Anal. Calc'd for C₂₆ H₄₀ ClN₃ O₄. 0.25 H₂ O: C, 63.63; H, 8.19; Cl,7.11; N, 8.43; Found: C, 62.76; H, 8.30; Cl, 6.82; N, 8.37.

EXAMPLE 12A [1S-[1α,2α(Z),3α,4α]]-N-(4-Cyclohexylbutyl)₂-[2-[5-(1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicyclo[2.2.1]-hept-3-vl]-4-oxazolecarboxamide

A.[1S-[1α,2α(),3α,4α]]-2-5-(1H-Tetrazol-5-yl)-2-pentenyl,]-7-oxabicyclo[2.2.1]heptane-3-methanol

To a 0° C. slurry, of 1.0 mmol[4aR-(4aα,5β,8β,8aα)-octahydro-5,8-epoxy-1H-2-benzopyran3-ol, preparedas described in U.S. Pat. No. 4,143,054, and 1.4 mmol3-(tetrazol-5-yl)propyltriphenylphosphonum bromide in tetrahydrofuran isadded dropwise a 1.8M solution of KOt-amylate in toluene (2.8 mmol). Themixture is allowed to warm to room temperature overnight. The reactionmixture is quenched by the addition of acetic acid. The reaction mixtureis concentrated in vacuo and purified by silica gel chromatography usingCH₃ OH/CH₂ Cl₂ mixture as eluants.

B.[1S-[1α,2α(Z),3α,4α]]-2-[5-(1-Methoxymethyl-1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicvclo[2.2.1]heptane-3-methanol

A solution of 1.0 mmol of title A tetrazole in THF is cooled to 0° C.and treated with 1.0 mmol of triethylamine and 1.0 mmol ofbromomethylmethyl ether. The mixture is stirred for 4 hours at roomtemperature and then partitioned between saturated aqueous NaHCO₃ andethyl acetate. The ethyl acetate layer is dried, filtered andconcentrated in vacuo to afford title B tetrazole.

C. [1S-[1α,2α(Z),3α,4α]]-N-(4-Cyclohexylbutyl)-2-[2-[5-(1-methoxymethyl-1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicyclo2.2.1]hept-

3-yl]-4-oxazolecarboxamide

Following Example lA except substituting Example 12A, Part B tetrazolefor Example lA, Part C ester, the title compound is obtained.

D.[1S-[1α,2α(Z),3α,4α]]-N-(4-Cyclohexylbutyl)-2-[2-[5-(1H-tetrazol-5-yl)-2-pentenyl]-7-oxabicyclo[2.2.1]hept-3-yl]-4-oxazolecarboxamide

To a solution 1.0 mmol of title C tetrazole in CH₃ OH (25 mL) is added 1drop of concentrated HCl solution. The solution is heated to reflux for2 hours. On cooling, the reaction mixture is concentrated in vacuo. Thecrude product is purified by reverse-phase HPLC using CH₃ CN/0.02%aqueous H₃ PO₄ mixtures as the mobile phase to afford title tetrazole.

Examples of additional compounds in accordance with the presentinvention which may be prepared following the procedures outlined in thespecification and working Examples include, but are not limited to thefollowing:

    __________________________________________________________________________     ##STR185##                                                                          (CH.sub.2).sub.m                                                                  (CH.sub.2).sub.n                                                   Example No.                                                                           .sub.--m                                                                          -n X  R.sup.1      R.sup.2                                                                            R                                         __________________________________________________________________________    13A    1   2   O  C.sub.6 H.sub.13                                                                           CH.sub.3                                                                           CO.sub.2 H                                14A    2   2   O                                                                                 ##STR186##  C.sub.2 H.sub.5                                                                    CO.sub.2 H                                15A    3   1   NH                                                                                ##STR187##  i-C.sub.3 H.sub.7                                                                  CONHSO.sub.2 CH.sub.3                     16A    1   2   S                                                                                 ##STR188##  H    CH.sub.2 -5-tetrazolyl                    17A    2   3   O  C.sub.6 H.sub.5                                                                            C.sub.6 H.sub.5                                                                    CO.sub.2 H                                18A    1   2   NH CH.sub.2 C.sub.6 H.sub.5                                                                   CH.sub.2 C.sub.6 H.sub.5                                                           CONHC.sub.6 H.sub.5                       19A    1   2   O  i-C.sub.3 H.sub.7                                                                          H    CONHSO.sub.2 C.sub.6 H.sub.5              20A    1   3   O                                                                                 ##STR189##  n-C.sub.4 H.sub.9                                                                  CONHSO.sub.2 CH.sub.2 C.sub.6                                                 H.sub.5                                   21A    1   2   NH                                                                                ##STR190##  H    CONHCH.sub.2 C.sub.6 H.sub.5              22A    2   2   O                                                                                 ##STR191##  CH.sub.2 C.sub.6 H.sub.5                                                           CO.sub.2 CH.sub.3                         23A    1   2   S  C.sub.2 H.sub.5                                                                            H    CO.sub.2 Li                               24A    1   3   NH                                                                                ##STR192##  C.sub.2 H.sub.5                                                                    CO.sub.2 C.sub.2 H.sub.5                  25A    1   2   O  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                           CH.sub.3                                                                           CO.sub.2 H                                26A    1   3   O  n-C.sub.3 H.sub.7                                                                          CH.sub.2 C.sub.6 H.sub.5                                                           CH.sub.2 -5-tetrazolyl                    27A    1   2   NH n-C.sub.5 H.sub.11                                                                         H    CO.sub.2 H                                28A    2   3   O                                                                                 ##STR193##  CH.sub.3                                                                           CONHCH.sub.3                              29A    1   2   O                                                                                 ##STR194##       CONH.sub.2                                __________________________________________________________________________

EXAMPLE 30A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-Cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A. Benzenepentanol, methanesulfonate ester

To a stirred solution of 5-phenyl-1-pentanol (5.0 g, 30.4 mmol) in 20 mLof methylene chloride at -70° C. under argon, was added first (C₂ H₅)₃ N(4.0 g, 39.5 mmol), then methanesulfonyl chloride (2.83 mL, 4.18 g, 36.5mmol) dropwise. The reaction mixture was slowly warmed to roomtemperature. After stirring for 2 hours at room temperature, water wasadded, and the reaction mixture was extracted with methylene chloride(50 mL). The aqueous layer was extracted twice more with CH₂ Cl₂ (25mL). The organic layers were combined and washed with brine, dried overMgSO₄, and concentrated to obtain 7.30 g (100%) of title compound in theform of a yellow oil. R_(f) 0.9 in 50% hexane-ethyl acetate (UV,Ce(SO₄)₂)

¹³ C NMR (CDCl₃) 6 141.9, 128.2, 125.6, 69.9, 37.1, 35.5, 30.6, 28.8,24.8.

B. Benzenehexanenitrile

To a stirred solution of Part A compound (7.30 g, 30.1 mmol) in 70 mL ofC₂ H₅ OH at room temperature was added a solution of KCN (9.81 g, 150.6mmol) in 29 mL of water. This reaction mixture was stirred for 20 hours,then extracted with CHCl₃ three times (50 mL). The organic layers werecombined and washed with water, then brine, and dried over MgSO₄ andconcentrated in vacuo to obtain a yellow oil containing title compoundand remaining Part A compound. This oil was purified by flashchromatography (95:5 hexane-ethyl acetate) to obtain 2.16 g (41%) of thedesired title product as an oil.

¹³ C NMR (CDCl₃): δ 141.8, 128.0, 125.5, 119.5, 35.4, 30.5, 27.9, 24.9,16.7.

C. Cyclohexanehexanamine

To a stirred solution of Part B compound (2.16 g, 12.4 mmol) in 100 mLof CH₃ COOH was added PtO₂ (0.60 g). The mixture was stirred at roomtemperature under H₂ balloon at 1 atmosphere. After 20 hours thereaction mixture was filtered through a celite pad, and the pad waswashed with ethanol twice. The filtrate was concentrated in vacuo toobtain a semi-solid. This was stirred in hexane, and title product inthe form of a white fluffy solid (2.00 g, 95%) was obtained byfiltration.

D.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-Cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A sample of 1.61 g of Example 2A, Part G oxazole acid (4.8 mmol) wasdried by azeotroping with dry DMF and toluene twice (high vacuum). Thismaterial (which contained residual DMF) was dissolved in 30 mL toluene,and while stirring at room temperature under argon, 2.9 g oxalylchloride (23 mmol) was added. Gas was evolved. A dark oil formed at thebottom of the reaction mixture. (The oil was the product of the reactionof DMF with oxalyl chloride.) After 5 minutes an additional 2.9 g oxalylchloride was added. This mixture was stirred overnight. TLC indicatedclean conversion to the acid chloride. The supernatant was pipetted offand transferred to an argon filled flask. Twice the oil was stirred withadditional toluene and the supernatant transferred. The combinedsupernatants were evaporated with CHCl₃ to provide 1.54 g (91% yield) ofthe acid chloride, namely[1S-[1α,2α(Z),3α,4α]]-6-[3-4-(chlorocarbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester.

To a solution of (0.55 g, 3.0 mmol) Part C amine in 5 mL of chloroformat 0° C., was added (0.3 g, 3.0 mmol) triethylamine and (0.53 g, 1.5mmol) the above acid chloride. The mixture was stirred at roomtemperature for 14 hours, then diluted with chloroform and water. Theorganic layer was separated, and the aqueous layer was extracted with 20mL of chloroform twice. The organic layers were combined, washed withbrine, dried over MgSO , and concentrated. Flash chromatography (0% to75% EtOAc in hexane gradient) gave 0.49 g of product as a clear oil in65% yield. R_(f) 0.5 in 1:1 hexane-ethyl acetate (UV, Ce(SO 4)₂)

¹³ C NMR (67.8 MHz, CDCl₃): δ 172.8, 163.5, 160.1, 140.1, 135.8, 129.1,128.2, 79.2, 79.0, 51.0, 49.4, 46.3, 38.7, 37.2, 37.0, 33.4, 33.0, 29.4,29.2, 28.6, 27.5, 26.6, 26.3, 26.1, 22.5.

EXAMPLE 31A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-Cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A solution of (0.49 g, 0.97 mmol) Example 30A ester in 8 mL of 1N NaOHand 8 mL of THF was stirred for 18 hours, then concentrated in vacuo toremove THF and acidified to pH 1.5 with 1N HCl. Ethyl acetate was addedand the organic layer was separated. The aqueous layer was extractedtwice with 20 mL ethyl acetate. The organic layers were combined, washedwith brine, dried over MgSO₄, and concentrated in vacuo. A white solidwas obtained. This was crystallized from hexane and chloroform to give0.40 g (84%) of pure product as a white solid. R_(f) 0.36 in 0.1% CH₃COOH in (4% methanol in ethyl acetate). Visualized by UV: Ce(SO₄)₂.[α]_(D) °=+30.2, c 0.58 g/100 mL of CH₃ OH, mp 82°-83° C.

EXAMPLE 32A [1S-[1α,2α(Z),3β,4α]]-6-[3-[4-[[(6-Cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoicacid, methyl ester

To a stirred solution of 0.49 g (1.40 mmol) acid chloride prepared asdescribed in Example 2A, Part I plus an unknown quantity of Vilsmeiersalt in 10 mL of chloroform, was added 0.28 g (2.80 mmol) oftriethylamine and 0.38 g (2.1 mmol) of 6-cyclohexylhexylamine preparedin Example 30, Part C. The mixture was stirred at room temperature for10 hours, then diluted with ethyl acetate and water. The organic layerwas separated, and the aqueous layer was extracted with 20 mL of ethylacetate twice. The organic layers were combined, washed with brine,dried over MgSO₄, and concentrated. Flash chromatography (0% to 100%ethyl acetate-hexane gradient) gave 0.17 g of title product as a clearoil in 25% yield. R_(f) =0.46 in 1:1 ethyl acetate:hexane.

EXAMPLE 33A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(6-Cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A solution of 0.17 g (0.33 mmol) of Example 32A ester in 5 mL of 1N NaOHand 2 mL of tetrahydrofuran was stirred at room temperature for 10hours, then concentrated in vacuo to remove THF and acidified to pH 1.5with concentrated HCl. Ethyl acetate was added and the organic layer wasseparated. The aqueous layer was extracted twice with 20 mL ethylacetate. The organic layers were combined, washed with brine, dried overMgSO₄ and concentrated in vacuo. A clear oil was obtained. This waschromatographed in 1:1 EtOAc-hexane with 0.25% CH₃ COOH to give 0.13 g(78%) of title product as an oil (containing 2.5% of the cis isomer ofExample 31A compound). R_(f) =0.36 in 4% CH₃ OH, 0.1% CH₃ COOH, 95.5%EtOAc (UV, Ce(SO₄)₂) [α]_(D) °=+55° in CH₃ OH at c=0.50 g/ 100 mL.

EXAMPLE 34A[1α,2α(Z),3α,4α]-6-[3-[4-(1-Pyrrolidinylcarbonyl)-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred solution of 0.18 g (0.50 mmol) of the acid chlorideprepared in Example 2A, Part I in 3 mL of chloroform at 0° C., underargon was added 0.10 g (1.0 mmol) of triethylamine and 0.07 g (1.0 mmol)of pyrrolidine. The mixture was warmed to room temperature and stirredfor 10 hours, then diluted with ethyl acetate and water. The organiclayer was separated, and the aqueous layer was extracted with 20 mL ofethyl acetate twice. The organic layers were combined, washed withbrine, dried over MgSO₄, and concentrated. Flash chromatography (50% to100% ethyl acetate in hexane gradient then 2% methanol in ethyl acetate)gave 0.13 g of title product as a clear oil in 68% yield. R_(f) =0.6 in9:1 ethyl acetate-methanol (UV, Ce(SO₄)₂).

¹³ C NMR (67.8MHZ, CDCl₃): δ 172.9, 162.9, 160.0, 141.9, 136.9, 129.0,128.5, 79.2, 78.9, 51.1, 49.4, 47.9, 46.5, 46.4, 33.5, 29.5, 28.7, 27.6,26.1, 23.4, 22.5.

EXAMPLE 35A[1α,2α(Z),3α,4α]-6-3-[4-(1-Pyrrolidinylcarbonyl)-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid

A solution of 0.13 g (0.33 mmol) of Example 34A compound in 10 mL of 1NNaOH and 2 mL of tetrahydrofuran was stirred for 10 hours at roomtemperature, then concentrated in vacuo to remove THF and acidified topH 1.5 with 1N HCl. Ethyl acetate was added and the organic layer wasseparated. The aqueous layer was extracted twice with 20 mL ethylacetate. The organic layers were combined, washed with brine, dried overMgSO₄ and concentrated in vacuo. A clear oil was obtained. This waschromatographed (EtOAc then 1% CH₃ OH, 0.25% CH₃ COOH, 98.75% EtOAc) togive 0.12 g (92%) of pure product as an oil. R_(f) =0.2 in 1% CH₃ OH,0.5% CH₃ COOH, 98.5% EtOAc. [α]°_(D) =+35.7° in CH₃ OH at c=2.40 g/100mL.

EXAMPLE 36A[1S-[1α,2α(Z),3α,4α]-6-[3-[4-[(Propylamino)carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of (0.22 g, 3.7 mmol) propylamine in 5 mL of chloroform at0° under argon, was added 0.162 g, (0.46 mmol) acid chloride prepared asdescribed in Example 2A, Part I. The mixture was warmed to roomtemperature and stirred for 14 hours, then diluted with chloroform andwater. The organic layer was separated and the aqueous layer wasextracted with 20 mL of chloroform twice. The organic layers werecombined, washed with brine, dried over MgSO₄, and concentrated. Flashchromatography (0% to 75% EtOAc in hexane gradient) gave 0.15 g of titleproduct as a clear oil in 85% yield. R_(f) 0.29 in 4% methanol in ethylacetate (UV, Ce(SO₄)₂).

¹³ C NMR (CDCl₃): δ 173.0, 163.7, 160.4, 140.2, 136.0, 129.2, 128.4,79.3, 79.2, 51.2, 49.5, 46.5, 40.5, 33.6, 29.6, 28.7, 27.7, 22.7, 22.6,11.2.

EXAMPLE 37A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(Propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A solution of 0.15 g (0.39 mmol) Example 36 ester in 8 mL of 1N NaOH and8 mL of THF was stirred for 18 hours, then concentrated in vacuo toremove THF and acidified to pH 1.5 with 1N HCl. Ethyl acetate was addedand the organic layer was separated. The aqueous layer was extractedtwice with 20 mL ethyl acetate. The organic layers were combined, washedwith brine, dried over MgSO₄ and concentrated in vacuo. A clear oil wasobtained. This was crystallized from hexane and chloroform to give 0.14g (100%) of pure product as a white solid. R_(f) 0.41 in 0.1% CH₃ COOH,4% methanol, 95.9% ethyl acetate (UV, Ce(SO₄)₂) mp 117°-118° C., []°_(D)=+42.12 at c 4.7 g/100 mL CH₃ OH.

EXAMPLE 38A [1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Butylphenyl)aminocarbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 0.189 g (1.27 mmol) 4-butylaniline in 5 mL ofchloroform under argon at 0° C., was added 0.17 g (0.48 mmol) acidchloride prepared as described in Example 2A, Part I and 0.145 g (1.44mmol) triethylamine. The mixture was warmed to room temperature andstirred for 14 hours, then diluted with chloroform and water. Theorganic layer was separated, and the aqueous layer was extracted with 20mL of chloroform twice. The organic layers were combined, washed withbrine, dried over MgSO₄, and concentrated. Flash chromatography (0% to75% EtOAc in hexane gradient) gave 0.16 g of title product as a clearoil in 69% yield. R_(f) 0.87 in 4% methanol in ethyl acetate (UV, Ce(SO)₂).

¹³ C NMR (CDCl₃) 6 173.1, 163.9, 158.2, 141.1, 139.0, 136.2, 129.4,128.7, 128.4, 119.7, 79.4, 79.3, 51.3, 49.6, 46.6, 34.9, 33.6, 33.5,29.7, 28.8, 27.8, 22.7, 22.1, 13.8.

EXAMPLE 39A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Butylphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid

A solution of 0.16 g (0.34 mmol) Example 38A ester in 8 mL of 1N NaOHand 8 mL of THF was stirred for 18 hours, then concentrated in vacuo toremove THF and acidified to pH 1.5 with 1N HCl. Ethyl acetate was addedand the organic layer was separated. The aqueous layer was extractedtwice with 20 mL ethyl acetate. The organic layers were combined, washedwith brine, dried over MgSO₄ and ccncentrated in vacuo. A clear oil wasobtained. This was crystallized from hexane and chloroform to give 0.13g (87%) of pure product as a yellow solid. R_(f) 0.47 in 0.1% CH₃ COOH,4% methanol, 95.9% ethyl acetate (UV, Ce(SO₄)₂) mp 113°-114° C. [α]°_(D)=+6.44, 0.59 g/100 mL of CH₃ OH.

EXAMPLE 40A[1S-[1α,2α(Z),3α,4α]]-6-3-[4-[(2,3-Dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 0.18 g (1.50 mmol) indoline in 5 mL of chloroform, wasadded 0.18 g (1.8 mmol) triethylamine and 0.46 g (1.30 mmol) acidchloride prepared as described in Example 2A, Part I. The mixture wasstirred at room temperature for 14 hours, then diluted with chloroformand water. The organic layer was separated, and the aqueous layer wasextracted with 20 mL of chloroform twice. The organic layers werecombined, washed with brine, dried over MgSO₄, and concentrated. Flashchromatography (0% to 75% EtOAc in hexane gradient) gave 0.37 g of titleproduct as a yellow oil in 65% yield. R_(f) 0.8 in 98.9% ethyl acetate,1% methanol, 0.1% TFA (UV, Ce(SO₄)₂).

EXAMPLE 41A[1S-[1α,2α(Z),3α,4α]]-6-[3-4-(2,3-Dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-vl]-4-hexenoic acid

A solution of 0.37 g (0.80 mmol) of Example 40A ester in 15 mL of 1NNaOH and 15 mL of methanol was stirred for 18 hours, and acidified to pH2 with concentrated HCl. Ethyl acetate was added and the organic layerwas separated. The aqueous layer was extracted twice with 20 mL ethylacetate. The organic layers were combined, washed with brine, dried overMgSO₄, and concentrated in vacuo. A red oil was obtained. This waschromatographed (0.1% CH₃ COOH in (0% to 100% EtOAc in hexane gradient))to give 0.25 g (75%) of pure title product as a yellow oil. R_(f) 0.29in 0.1% CH₃ COOH in 50% ethyl acetate in hexane (UV, Ce(SO₄)₂) [α]°_(D)=+31.2 in CH₃ OH at c 0.48 g/100 mL.

EXAMPLE 42A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide

To a stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,hydrochloride salt (102 mg, 0.50 mmol) and 4-dimethylaminopyridine (66.7mg, 0.50 mmol) in 50 mL of DMF was added benzenesulfonamide (80 mg, 0.51mmol) and (C₂ H₅)₃ N (0.14 mL, 1.00 mmol) followed by Example lA acid(229 mg, 0.50 mmol). The mixture was stirred at room temperature for 18hours and concentrated in vacuo. The residue was partitioned between 25mL of 1N HCl solution and EtOAc (4×40 mL). The combined EtOAc extractswere washed with 30 mL of brine, dried (MgSO₄), filtered andconcentrated in vacuo. This was chromatographed on 30 g of Merck silicagel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 250 mg of titlesulfonamide. This product was partitioned between 60 mL of EtOAc and H₂O. (1×20 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to give 210 mg of title compound as a solid. m.p.154°-156° C., (70%) TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.46,Ce(SO₄)₂.

¹³ C NMR title compound (CDCl₃, 67.5 MHz): δ 171.1, 170.5, 163.9, 161.1,140.7, 139.0, 135.9, 133.5, 128.7, 128.2, 79.7, 79.7, 49.5, 46.4, 39.2,37.4, 37.0, 35.9, 33.3, 33.3, 29.7, 28.8, 27.9, 26.6, 26.3, 26.3, 24.1,22.3.

EXAMPLE 43A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenamide

To a stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,hydrochloride salt (102 mg, 0.50 mmol) and 4-dimethylaminopyridine (66.7mg, 0.50 mmol) in 50 mL of DMF was added methanesulfonamide (47.6 mg,0.50 mmol) and (C₂ H₅)₃ N (0.14 mL, 1.00 mmol) followed by Example 1Aacid (229 mg, 0.50 mmol). The mixture was stirred at room temperaturefor 18 hours and concentrated in vacuo. The residue was partitionedbetween 25 mL of 1N HCl solution and EtOAc (4 times with 40 mL). Thecombined EtOAc extracts were washed with 30 mL of brine, dried (MgSO₄),filtered and concentrated in vacuo. This was chromatographed on 30 g ofMerck silica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 200 mgof title sulfonamide. This product was partitioned between 60 mL ofEtOAc and H₂ O (1×20 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo to give 150 mg (56%) of title compound as asolid. m.p. 140°-142° C., TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f)0.40, Ce(SO₄)₂.

¹³ C NMR title compound (CDCl₃, 67.5 MHz): δ 171.8, 163.9, 161.0, 140.8,135.9, 128.8, 128.7, 79.7, 79.7, 49.5, 46.4, 41.3, 39.2, 37.4, 37.0,36.0, 33.3, 33.3, 29.7, 28.8, 28.0, 26.6, 26.3, 26.3, 24.1, 22.3.

EXAMPLE 44A[1S-[1α,2α(Z),3α,4α]]-7-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-yl]-5-heptenoicacid, methyl ester

A.[1S-[1α,2α(Z),3α,4α]]-7-(3-Carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid

To a stirred solution of[1S-[1α,2α(Z),3α,4α]]-7-(3-hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester (1.60 g, 5.97 mmol) in 100 mL of acetone at 0° C. wasadded MnSO₄ treated Jones reagent (about 100 mg MnSO₄ dissolved in 100mL of Jones reagent) until an orange-red color persisted. The mixturewas stirred at 0° C. for 30 minutes and at room temperature for 1.5hours. The mixture was quenched with isopropyl alcohol (IPA) andconcentrated in vacuo. The residue was partitioned between 70 mL of 3MNaHSO₃ solution and EtOAc (4×100 mL). The combined EtOAc extracts werewashed with H₂ O (1×70 mL) and brine (1×70 mL). The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo to give 1.57 g (93%)of title acid which was used for the next transformation without furtherpurification. TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.24, Ce(SO₄)₂.

¹³ C NMR title acid (CDCl₃, 67.5 MHz): δ 176.7, 174.0, 130.5, 128.3,78.4, 78.2, 51.8, 51.3, 47.8, 33.3, 29.0, 28.7, 27.2, 26.6, 24.6.

B. [2-[(4-Cyclohexylbutyl)amino)-1-(hydroxymethyl)-2-oxoethyl]carbamicacid, 1,1-dimethylethyl ester

To a stirred mixture of 4-cyclohexylbutylamine.HCl salt (19.5 g, 102mmol), 1-hydroxybenzotriazole.H₂ O (16.5 g, 122 mmol) and Boc-L-serine(25.0 g, 122 mmol) in 400 mL of DMF under argon at 0° C. was addedsequentially C₂ H₅)₃ N (42.5 mL, 305 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide.HCl salt (23.4 g, 122mmol). The mixture was stirred at 0° C. for 1 hour and at roomtemperature for 18 hours. The mixture was concentrated in vacuo anddiluted with 800 mL of EtOAc. The resulting solution was washed with 1NHCl solution (3 times with 120 mL), 0.2N NaOH solution (2 times with 100mL), saturated NaHCO₃ solution (1 time with 100 mL) and brine (1 timewith 150 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo to give 39.9 g of title amide in a quantitativeyield. TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.38, Ce(SO₄)₂.

¹³ C NMR title amide (CDCL₃, 67.5 MHz): δ 171.2, 156.2, 80.3, 62.8,39.6, 37.4, 37.0, 33.3, 29.6, 28.2, 26.6, 26.3, 24.0.

C.[1S-[1α,2α(Z),3α,4α]]-7-3-[[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester

To a stirred solution of Part B amide (1.90 g, 5.56 mmol) in 20 mL ofCH₂ Cl₂ at 0° C. was added 8 mL of trifluoroacetic acid (TFA). Thismixture was stirred at 0° C. for 3 hours. The mixture was diluted with50 mL of toluene and concentrated in vacuo to give amine.TFA salt. To astirred solution of this amine.TFA salt, Part A acid (1.57 g, 5.57 mmol)and 1-hydroxybenzotriazole.H₂ O (0.75 g, 5.57 mmol) in 60 mL of DMF at0° C. under argon was added sequentially (C₂ H₅)₃ N (3.88 mL, 27.8 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCL salt (1.07 g, 5.57mmol). This mixture was then stirred at room temperature for 16 hoursand concentrated in vacuo. The crude product was diluted with 400 mL ofEtOAc and washed with 1N HCl solution (3 times with 70 mL), 0.2N NaOHsolution (2 times with 50 mL) and saturated NaHCO₃ solution (1 time with50 mL). The organic layer was dried (MgSO₄), filtered and concentratedin vacuo. This was chromatographed on 70 g of Merck silica gel 60 using2% CH₃ OH in CH₂ Cl₂ as eluant to give 1.74 g (42%) of title alcohol.TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.18, Ce(SO₄)₂.

¹³ C NMR title alcohol (CDCl₃, 67.5 MHz): δ 174.0, 173.2, 170.6, 130.6,128.5, 79.2, 79.0, 62.7, 54.4, 53.5, 51.4, 48.0, 39.5, 37.4, 37.0, 33.3,33.3, 33.3, 29.6, 28.6, 27.5, 26.6, 26.3, 26.3, 24.7, 24.1.

D.[1S-[1α,2α(Z),3α,4α]]-7-[3-[5-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester

To a stirred solution of Part C alcohol (1.10 g, 2.17 mmol) and (C₂ H₅)₃N (0.61 mL, 4.35 mmol) in 10 mL of dry CH₂ Cl₂ at 0° C. was addedmethanesulfonyl chloride (0.20 mL, 2.61 mmol). This mixture was stirredat 0° C. under argon atmosphere for 1.5 hours and diluted with 200 mL ofCH₂ Cl₂. This mixture was washed with saturated NaHCO₃ solution (1 timewith 20 mL) and brine (1 time with 20 mL). The organic layer was dried(MgsO₄), filtered and concentrated in vacuo. The crude product wasdissolved in 20 mL of acetone and combined with 1.40 g of K₂ CO₃. Themixture was refluxed for 5 hours and cooled to room temperature. Theprecipitate was filtered through a 2 inch pad of Celite® and rinsed withacetone (4 times with 50 mL). The filtrate was concentrated in vacuo.Purification was effected by flash chromatography on 36 g of Mercksilica gel 60 using 2% CH₃ OH in CH₂ Cl₂ as eluant to give 740 mg (70%)of title oxazoline. TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) 0.48,Ce(SO₄)₂.

¹³ C NMR title compound (CDCl₃, 67.5 MHz): δ 173.7, 171.2, 169.2, 130.5,128.4, 79.0, 79.0, 69.6, 68.3, 51.3, 48.3, 46.3, 39.0, 37.4, 36.9, 33.3,33.2, 33.2, 29.7, 29.6, 28.8, 27.2, 26.6, 26.5, 26.2, 26.2, 24.6, 24.0.

E.[1S-[1α,2α(Z),3α,4α]]-7-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester

To a stirred solution of Part D oxazoline (730 mg, 1.50 mmol) in 15 mLof dry CH₂ Cl₂ was added 1.10 g of NiO₂. This mixture was stirred atroom temperature for one hour, then 0.74 g of NiO₂ was added. Thismixture was stirred at room temperature for an additional hour and asecond portion of 0.74 g of NiO₂ was added. This mixture was stirred atroom temperature for one more hour and then diluted with 80 mL of EtOAc,50 mL of 3M NaHSO₃ solution and 50 mL of 1M sodium citrate solution. Theaqueous layer was separated and extracted with EtOAc (3×120 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. This was chromatographed on 30 g of Merck silica gel 60 using2% CH₃ OH in CH₂ Cl₂ as eluant to give 410 mg (56%) of title oxazole.TLC: silica gel, 2% CH₃ OH/CH₂ Cl₂, R_(f) 0.31, Ce(SO₄)₂.

¹³ C NMR title compound (CDCl₃, 67.5 MHz): δ 173.7, 163.8, 160.5, 140.4,136.1, 130.5, 128.0, 79.5, 79.3, 51.3, 49.7, 46.6, 39.0, 37.4, 37.0,33.3, 33.3, 29.8, 29.7, 28.9, 27.8, 26.6, 26.3, 24.6, 24.1.

EXAMPLE 5A[1S-[1α,2α(Z),3α,4α]]-7-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-y]-5-heptenoic acid

To a stirred solution of Example 44A oxazole (410 mg, 0.84 mmol) in 20mL of CH₃ OH was added 5 mL of 1N NaOH solution. This mixture wasstirred at room temperature for 2.5 hours and concentrated in vacuo.This mixture was partitioned between 10 mL of 1N HCl solution saturatedwith NaCl and EtOAc (4 times with 20 mL). The EtOAc extracts were dried(MgSO₄), filtered and concentrated in vacuo. Purification was effectedby flash chromatography on 20 g of Merck silica gel 60 using 150 mL of2% CH₃ OH in CH₂ Cl₂ as eluant, followed with the elution of 4% CH₃ OHin CH₂ Cl₂ with 1% acetic acid to give 370 mg (93%) of pure title acid.m.p. 123°-125° C. TLC: silica gel, 6% CH₃ OH in CH₂ Cl₂, R_(f) 0.22,Ce(SO₄)₂.

¹³ C NMR title compound (CDCl₃, 67.5 MHz): δ 177.8, 164.0, 160.9, 140.9,135.8, 130.5, 128.1, 79.4, 79.4, 49.8, 46.7, 39.2, 37.5, 37.0, 33.3,33.3, 29.8, 28.9, 27.8, 26.6, 26.5, 26.3, 26.3, 24.4, 24.2.

EXAMPLE 46A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A. 3,3-Dimethylbutanal

A solution of oxalyl chloride (9.4 mL, 13.6 g, 107 mmol) under argon inCH₂ Cl₂ (500 mL) was prepared in a 1000 mL flask and cooled to -60° C. Asolution of DMSO (15.4 mL, 18.5 g, 235 mmol) in 25 mL of CH₂ Cl₂ wasadded dropwise over 10 minutes. The reaction mixture was stirred for 10minutes, and 3,3-dimethyl-1-butanol (10 g, 98 mmol) was added slowly.Stirring was continued for an additional 20 minutes before (C₂ H₅)₃ N(68.1 mL, 49.5 g, 489 mmol) was added, and then the reaction mixture wasallowed to warm to room temperature. Water (50 mL) was then added. Themixture was separated, and the aqueous layer was extracted once with CH₂Cl₂ (30 mL). The organic layers were combined, washed sequentially with1% aqueous HCl, water, saturated NaHCO₃, H₂ O, and saturated NaCl, anddried over MgSO₄. The filtered solution was concentrated using a rotaryevaporator to obtain 3.3 g (33%) of title compound in the form of ayellow oil. The low yield was probably due to product volatility.

¹³ C NMR (67.8 MHz, CDCl₃): δ 203.3, 56.4, 31.0, 29.7

B. (Z)-7,7-Dimethyl-4-octenoic acid

To a stirred solution of 3-carboxypropyltriphenyl phosphonium bromide(13.72 g, 31.9 mmol) in 60 mL of dry THF under argon at -15° C. wasadded dropwise 1.72N K t-amylate/toluene (32 mL, 57.9 mmol) over 10minutes. The orange colored mixture was stirred for 0.5 hours. To this,Part A aldehyde (2.00 g, 19.9 mmol) was added slowly as a solution in 5mL of THF. The reaction mixture was stirred at -15° C. for 1 hour and atroom temperature for 20 hours. The reaction mixture was quenched with 12mL of CH₃ COOH added dropwise and then concentrated in vacuo. Theresidue was partitioned between EtOAc (100 mL) and water (100 mL). Theaqueous layer was extracted twice more with EtOAc (100 mL). The combinedorganic layers were washed sequentially with 1% aqueous HCl, H₂ O,saturated NaHCO₃, H₂ O, and saturated NaCl, dried over MgSO₄ , andconcentrated in vacuo. The residue was chromatographed eluting with 0.3%CH₃ COOH in (1% to 100% EtOAc in hexane gradient) to obtain 1.75 g (51%)of the desired title product.

¹³ C NMR (CDCl₃): δ 179.8, 128.6, 128.4, 41.0, 34.1, 31.1, 29.2, 22.6.

C. 7,7-Dimethyloctanoic acid

To a stirred solution of Part B acid (1.2 g, 7.04 mmol) in 8 mL of CH₃COOH, was added 0.2 g of platinum oxide. This mixture was stirred for 14hours under 1 atmosphere of H₂ (balloon). The reaction mixture wasfiltered through a Celite® pad. The filtrate was concentrated in vacuo.The residue was diluted with 50 mL toluene and concentrated again. Thisprocess was repeated once more, to obtain 1.2 g (100%) of the desiredtitle product as oil.

D. 7,7-Dimethyloctanamide

To a stirred solution of Part C acid (1.21 g, 7.02 mmol) in 50 mL oftoluene was added 3 mL of oxalyl chloride. This reaction mixture wasstirred for 1 hour at room temperature under argon and concentrated invacuo. The residue was diluted with 20 mL of toluene and concentratedagain. This was repeated to remove traces of oxalyl chloride. Theresidue was stirred at room temperature under argon in 5 mL of CH₃ OHand (C₂ H₅)₃ N (1.17 mL, 8.43 mmol), and an excess of 9M methanolicammonia (2 mL) was added. After stirring for 16 hours, the reactionmixture was partitioned between 3 mL water and 20 mL EtOAc. The aqueouslayer was extracted twice more with EtOAc (20 mL). The combined organiclayers were washed with NaCl, dried over MgSO₄, filtered, andconcentrated in vacuo to obtain a semi-solid. The semi-solid wascrystallized by trituration with hexane to obtain 0.5 g (42%) of thedesired title product as a solid.

¹³ C NMR (CDCl₃): δ 176.3, 43.9, 35.9, 30.2, 30.1, 29.3, 25.5, 24.2.

E. 7,7-Dimethyloctanamine

To a solution of Part D amide (0.45 g, 2.62 mmol) in 50 mL of dry etherstirred under argon at 0° C. was added lithium aluminum hydride (0.11 g,2.88 mmol). Gas was evolved. The reaction mixture was stirred at roomtemperature for 4 days. While stirring vigorously, the reaction wascautiously quenched by addition of 0.02 mL of H₂ O, 0.02 mL of 15%aqueous NaOH, and 0.072 mL of H₂ O. A white precipitate formed. Afterstirring for 0.5 hours, the white precipitate was filtered, and thefiltrate was concentrated in vacuo to obtain 0.4 g (89%) of titlecompound in the form of a yellow oil. This oil was crystallized bytrituration with hexane and CHCl₃.

F.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of acid chloride prepared in Example 2A, Part I (0.46 g,1.3 mmol) plus an unknown quantity of Vilsmeier salt in 5 mL of CHCl₃under argon at room temperature, was added (C₂ H₅)₃ N (0.25 mL, 0.18 g,1.8 mmol) and Part E amine (0.24 g, 1.5 mmol). The reaction mixture wasstirred at room temperature for 16 hours, then diluted with EtOAc andwater. The organic layer was separated, and the aqueous layer wasextracted with 20 mL of EtOAc twice. The organic layers were combined,washed with brine, dried over MgSO₄ and concentrated. Flashchromatography (0% to 100% EtOAc in hexane gradient) gave 0.20 g (32%)of the desired title product as an oil. R_(f) is 0.8 in 1% TFA, 1% CH₃OH, 98% EtOAc.

¹³ C NMR (CDCl₃): δ 172.8, 163.6, 160.2, 140.1, 135.9, 129.1, 128.3,79.3, 79.1, 51.1, 49.4, 46.4, 43.9, 38.8, 33.5, 29.9, 29.5, 29.4, 29.1,28.7, 27.6, 26.7, 24.1, 22.5.

EXAMPLE 47A[1S-1α,2α(Z),3α,4α]]-6-[3-[4-[[(7,7-Dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A solution of Example 46A ester (0.20 g, 0.38 mmol) in 10 mL of 1N NaOHand 10 mL of THF was prepared. The reaction mixture was stirred for 13hours, then concentrated in vacuo to remove THF and acidified to pH 2with 1N HCl. EtOAc was added and the organic layer was separated. Theaqueous layer was extracted twice with 20 mL of EtOAc. The organiclayers were combined, washed with brine, and concentrated in vacuo toobtain a clear oil. This oil was chromatographed (0.1% CH₃ COOH in (0%to 50% EtOAc in hexane gradient)) to obtain 0.12 g (66%) of title acidin the form of a white solid. mp 68°-69° C. R_(f) is 0.18 in 1:1hexane-EtOAc with 0.05% CH₃ COOH.

[α]_(D) °=+31.1 in CH₃ OH at c=0.46 g/100 mL.

¹³ C NMR (CDCl₃): δ 176.8, 163.9, 160.7, 140.8, 135.7, 129.4, 128.4,79.5, 79.3, 49.6, 46.5, 44.0, 39.1, 33.6, 30.1, 29.6, 29.4, 29.3, 28.8,27.8, 26.8, 24.3, 22.5.

EXAMPLE 48A[1S-[1α,2α(E),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid

A.[1S-[1α,2α(Z),3α,4α]]-7-[3-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester

To a stirring solution of 20.57 g of[1S-[1α,2α(Z),3α,4α]]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, methyl ester (prepared as described in U.S. Pat. No. 4,143,054)(76.8 mmol) and 5.74 g imidazole (84.4 mmol, 1.1 equiv) in 100 mL CH₂Cl₂ under argon at 0°, was added 12.05 g t-butyldimethylsilyl chloride(79.8 mmol, 1.04 equiv). A precipitate formed. The mixture was warmed toroom temperature, and 10 minutes later it was diluted with diethyl ether(Et₂ O), washed with water three times and brine once, dried over Na₂SO₄, and concentrated by rotoevaporation and then high vacuum. Theresidue, 30.31 g of nearly pure title silyl ether, was used withoutfurther purification. The yield of title ester was roughly quantitative.

    ______________________________________                                        TLC (50% EtOAc in hexanes - anisaldehyde):                                    ______________________________________                                               starting material                                                                        0.21                                                               title ester                                                                              0.79                                                        ______________________________________                                    

B.[1S-(1α,2α,3α4α)]-3[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-7-oxobicyclo[2.2.1]heptane-2-acetaldehyde

A solution of 3031 g nearly pure Part A silyl ether (76.8 mmol) in 200mL CH₂ Cl₂ at -78° was treated with ozone until a blue color hadpersisted for 25 minutes. After purging excess O₃ with O₂, 48.0 g (CH₃)₂S (770 mmol, 10 equiv) was added, and the mixture was warmed to roomtemperature, After 1 hour stirring at room temperature, solvent andexcess (CH₃)₂ S were removed by rotoevaporation. ¹ H NMR of the crudematerial revealed incomplete reduction of the ozonide. Therefore, afterredissolving in CH₂ Cl₂ at room temperature, 20. 2 g triphenylphosphine(77 mmol, 1.0 equiv) was added. This mixture warmed due to exothermicreaction. After stirring overnight, most of the solvent was evaporated,and hexane was added to precipitate triphenylphospine oxide andtriphenylphosphine. The precipitate was filtered off, and the filtratewas concentrated before flash chromatography (5% to 15% EtOAc in hexanesgradient) allowed isolation of 16.31 g pure title aldehyde as an oil.

    ______________________________________                                        TLC (50% EtOAc in hexanes - anisaldehyde):                                    ______________________________________                                        Part A silyl ether  0.89                                                      title aldehyde      0.76                                                      methyl 5-oxopentanoate                                                                            0.51                                                      ______________________________________                                    

C.[1S-(1α,2α(E),3α,4α)]-4-[3-[[[(1,1-Dimethylethyl)dimethylsilyl[oxy]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2-butenoicacid, methyl ester

A flash containing 3.3 g (37.9 mmol) of LiBr was placed under vacuum andheated with a heat gun to drive off any moisture. On cooling, the flaskwas flushed with Ar, and 20 mL of CH₂ Cl₂ was added. To this stirredmixture as added a solution of 5.44 g (29.9 mmol) oftrimethylphosphonoacetate in 30 mL of CH₂ Cl₂ followed by 4.0 mL of (C₂H₅)₃ N (28.7 mmol). This mixture was stirred for 15 minutes after whicha solution of 5.4 (19.0 mmol max.) of crude Part B aldehyde in 35 mL ofCH₂ Cl₂ was added over 1 minute. This was accompanied by a slightexotherm and the formation of a sticky precipitate. This mixture wasstirred vigorously at room temperature overnight. The reaction mixturewas partitioned between 200 mL of hexane and 100 mL of 0.3M HCl. Theaqueous layer was extracted once with 100 mL of diethyl ether. Thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo. TLC analysis showed that the reaction had notgone to completion (40-50%). The residue was then dissolved in 50 mL ofCH₂ Cl₂, and to it was added 6.3 g (18.8 mmol) ofcarbomethoxymethylenetriphenylphosphorane. This solution was stirred atroom temperature for 22 hours and then concentrated in vacuo. Theresidue was triturated with diethyl ether and diluted with an equalvolume of hexane. The mixture was refrigerated for 2 hours, and then thesolid was removed by filtration. The filtrate was concentrated in vacuo.The crude product was purified by chromatography on 167 g silica gelusing a 4:1 hexane-diethyl ether as eluent to provide 5.9 g (91%) oftitle ester.

TLC: silica gel, 2:1 hexane-ether, R_(f) 0.6, vanillin.

¹³ C NMR (67.8 MHz in CDCl₃): δ 148.8, 121.8, 79.9, 78.8, 61.9, 51.4,44.8, 30.7, 29.5, 29.4, 25.9, 18.2, -5.4.

D.[1S-(1α,2α(E),3α,4α)]-4-[3-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2-buten-1-ol

A solution of 5.2 g (15.3 mmol) of Part C ester in 80 mL of THF wascooled to -78° C. To this stirred solution was added dropwise 50.0 mL ofa 1.5M DIBAL-H solution in toluene over a period of 20 minutes. Thereaction was stirred at -78° C. for 5 hours, and then the reaction wasquenched by the addition of a solution of 10 mL of acetone in 10 mL oftoluene. This was followed by the slow addition of 60 g of 10:9 (w/w)silica gel:water. After several grams of the moist silica gel had beenadded, the cold bath was removed. The reaction mixture as diluted with200 mL of ether. The pot temperature was monitored, and when it reached10° C., the flask was immersed in an ice bath. This was stirred for 1hour, and then the silica gel was removed by filtration. The filter cakewas rinsed with two 100 mL portions of ether. The combined filtrateswere dried over MgSO₄, filtered, and concentrated in vacuo to afford5.05 g (>100%) of crude title alcohol.

TLC: silica gel, 2:1 hexane-ether, R_(f) 0.1, vanillin.

¹³ C NMR (67.8 MHz in CDCl₃): δ 131.6, 130.3, 79.8, 78.8, 63.3, 61.8,49.3, 45.4, 30.5, 39.5, 29.3, 25.9, 18.2, -5.4.

E.[1S-(1α,2α(E),3α,4α)]-4-[3-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-7-oxabicyco[2.21]hept-2-yl]-2-butene-1-bromide

To a flask containing 0.83 g of triphenylphosphine (3.17 mmol, 1.0equiv) dissolved in 10 mL toluene under argon at 0°, was added 0.51 g ofBr₂ (3.17 mmol, 1.0 equiv) in a single portion. A yellowish precipitateand an orange gum formed. Scraping with a spatula converted the gum tomore free flowing precipitate. The mixture was briefly warmed to roomtemperature, then recooled to 0°. To this was added dropwise a solutionof 1.04 g of Part D alcohol (95% pure=0.99 g, 3.17 mmol) and 0.28 g ofpyridine (3.49 mmol, 1.1 equiv) in 5 mL toluene plus a 5 mL wash-in. Themixture was stirred at 0° for 30 minutes, then warmed to roomtemperature. Reaction was incomplete according to TLC. After 4 hours (nofurther progress by TLC), the mixture was filtered, and the filtrate wasevaporated. Flash chromatography (3% to 50% EtOAc in hexanes gradient)allowed isolation of 880 mg of title bromide, an oil, and 190 mg ofunreacted Part D alcohol. The yield of title bromide was 74%.

    ______________________________________                                        TLC (25% EtOAc in hexanes - anisaldehyde):                                    ______________________________________                                               Part D alcohol                                                                          0.21                                                                title bromide                                                                           0.75                                                         ______________________________________                                    

⁻⁻ _(C) NMR (67.8 MHz in CDCl₃): δ 135.6, 126.5, 79.8, 78.8, 61.8, 49.4,45.3, 33.1, 30.5, 29.5, 29.4, 25.9, 18.2, -5.3.

F. [1S-(1α,2α(E),3α,4α)]-6-[3-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, 1,1-dimethylethyl ester

To a solution of LDA in THF (2.70 mmol, 1.15 equiv, prepared by slowlyadding 1.08 mL of 2.5M C₄ H₉ Li in hexanes solution (2.70 mmol, 1.15equiv) to a solution of 303 mg diisopropyl amine (3.0 mmol, 1.28 equiv)in 4 mL dry THF stirring at 0° under argon and then stirring for 15minutes) stirring under argon at -78° was added dropwise a solution of348 mg of t-butyl acetate (t-BuOAc) (3.0 mmol, 1.28 equiv) in 3 mL dryTHF over 15 minutes. After stirring 1 hour, a solution of 880 mg Part Ebromide (2.35 mmol) in 3 mL dry THF was added dropwise with two 2 mLwash-ins. After 8 hours of stirring at -78°, TLC showing only partialreaction, the mixture was allowed to very slowly warm (approximately 8°per hour) to room temperature. TLC indicated further progress, but stillincomplete consumption of bromide. Addition of 1 mL of saturated aqueousNH₄ Cl solution was followed by drying over Na₂ SO₄ and evaporation. Theresidue was flash chromatographed (5% EtOAc in hexane) to obtain 550 mgof nearly pure title ester product (97% pure=534 mg). The yield of titleester was 55%.

    ______________________________________                                        TLC (5% EtOAc in hexanes - anisaldehyde):                                     ______________________________________                                               Part E bromide                                                                          0.20                                                                title ester                                                                             0.13                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): δ 172.4, 130.6, 129.6, 80.0, 79.8, 78.8,61.9, 49.4, 45.8, 35.4, 30.8, 29.6, 29.4, 28.1, 25.9, 18.2, -5.3.

G.1S-(1α,2α(E),3α,4α)]-6-[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 550 mg of nearly pure Part F ester (97% pure=534 mg,1.30 mmol) in 20 mL CH₃ OH stirring at room temperature under argon, wasadded 2 mL of a solution of dry HCl in CH₃ OH (prepared by adding 2drops of acetyl chloride to 2 mL CH₃ OH at room temperature and thenallowing to stand 1 minute). TLC indicated complete conversion to anintermediate after 1 hour. This, intermediate was then very slowlyconverted to product. Addition of 10 mL more HCl in CH₃ OH solutionhastened the reaction. After 14 days, 2 mL (C₂ H₄)₃ N was added, and themixture was evaporated. This gave 630 mg of crude title alcohol.

    ______________________________________                                        TLC (50% EtOAc in hexanes - anisaldehyde):                                    ______________________________________                                               Part F ester                                                                           0.94                                                                 intermediate                                                                           0.33                                                                 title alcohol                                                                          0.23                                                          ______________________________________                                    

H.[1S-(1α,2α(E),3α,4α)]-6-[3-Carboxy-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a solution of 630 mg of crude Part G alcohol in 20 mL acetone underargon at 0°, was added slowly 4 mL Jones' Reagent (2.6M in Cr^(VI)). Thered color of the reagent persisted toward the end of the addition. Theresulting precipitated mixture was allowed to warm to room temperaturefor 20 minutes before recooling and 2-propanol addition to quench excessreagent. Still at 0°, 3M aqueous NaHSO₃ solution was added with stirringuntil all salts dissolved. Brine was added, and extraction (3 times)with EtOAc followed. After drying the extracts over Na₂ SO₄ and solventevaporation, flash chromatography (silica, 25% to 50% (5% acetic acid inEtOAc) in hexane gradient) afforded, after azeotropic removal of aceticacid with toluene, 260 mg of title acid, obtained in 75% overall yieldfrom Part F ester.

    ______________________________________                                        TLC (50% (5% CH.sub.3 COOH in EtOAc) in hexane -                              anisaldehyde):                                                                ______________________________________                                               Part G alcohol                                                                          0.32                                                                title acid                                                                              0.36                                                         ______________________________________                                    

¹³ C NMR (67.8 MHz in CDCl₃): δ 177.1, 173.4, 130.4, 129.2, 78.2, 78.1,51.9, 51.3, 47.4, 33.8, 32.4, 28.9, 28.8, 27.7.[1S-[1α,2α(E),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-

7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid

Following the procedure of Example 1A, starting at Part E exceptsubstituting the Part H acid for the Example 1, Part D acid, the titlecompound is obtained. mp 122°-125°; TLC (50% [5% AcOH in EtOAc]inhexane; title acid R_(f) 0.33%

¹³ C NMR (CDCl₃, 67.8 MHz): δ 176.9, 163.9, 160.7, 140.8, 135.6, 130.0,128.8, 79.4, 79.1, 49.1, 46.5, 39.1, 37.4, 36.9, 33.7, 33.2, 33.0, 29.7,29.5, 28.8, 27.5, 26.5, 26.2, 24.0.

EXAMPLE 49A[1S-(1α,2α,3α,4α)]-3-[4-[[(4-(Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-heptane-2-hexanoicacid

A solution of 130 mg of Example 1A acid in 10 mL of ethyl acetate and1.0 mL of acetic acid was degassed via a vacuum-fill cycle with argon.To this solution was added 34 mg of 10% Pd/C and the atmosphere wasexchanged for hydrogen by two vacuum-fill cycles. A slight positivepressure was maintained through use of a hydrogen balloon. The mixturewas stirred at room temperature for 22.5 hours, diluted with CH₂ Cl₂ andfiltered through a polycarbonate filter to remove the catalyst. Thefiltrate was concentrated in vacuo. The residue was diluted with tolueneand reconcentrated. Upon addition of ethyl acetate to the residue, asmall amount of gel-like material did not dissolve The solution wasdecanted off and concentrated in vacuo. The crude product was dissolvedin minimal hot ethyl acetate and diluted with ca. three volumes ofhexane. On cooling no solid appeared, however, after standing at 5° C.overnight a white gel-like solid formed. This was removed by filtrationand dried in vacuo. The resulting white powder was triturated in hexane,filtered and dried in vacuo to afford 61 mg of pure title acid; m.p.97(softens), 122°-3° C.

Analysis Calc'd for C₂₆ H₄₀ N₂ O₅ : C, 67.79; H, 8.75; N, 6.08; Found:C, 67.58; H, 8.79; N, 5.97

TLC: silica gel, 4% CH₃ OH/CH₂ Cl₂, R_(f) =0.35, Ce(SO₄)₂.

[α]_(D) =+23 (c=0.68, CHCl₃).

¹³ C NMR (CDCl₃, 67.5 MHz): δ 164.2, 160.8, 140.7, 135.9, 79.5, 79.4,49.8, 47.2, 39.2, 37.5, 37.1, 33.7, 33.4, 29.9, 29.7, 29.2, 29.0, 28.1,26.7, 26.4, 24.5, 24.2.

EXAMPLE 50A[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

A.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[[2-[(4-Cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]amino]carbonyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred mixture of Example 1A, Part D acid (6.70 g, 25.2 mmol),1-hydroxybenzotriazole monohydrate (3.40 g, 25.2 mmol) and TFA salt ofExample 1, Part B amine (8.97 g, 25.2 mmol) in 100 mL of DMF under argonat 0° C. was added sequentially C₂ H₅)₃ N (17.6 mL, 126 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (4.82g, 25.2 mmol). The mixture was stirred at 0° C. for 2 hours and at roomtemperature for 16 hours. The mixture was concentrated in vacuo andpartitioned between 800 mL of EtOAc and 1N HCl solution (2×100 mL), 0.2NNaOH solution (2×100 mL), saturated NaHCO₃ solution (1×100 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo.This was chromatographed on 180 g of Merck silica gel 60 using 2% CH₃OH/CH₂ Cl₂ as eluant to give 4.75 g (39%) of title amide.

TLC: silica gel, 50% (5% AcOH in EtOAc) in hexane, R_(f) 0.22,anisaldehyde.

B.[1S-[1α,2α(Z),3α(R*),4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-4,5-dihydro-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, methyl ester

To a stirred mixture of Part A amide (4.69 g, 9.53 mmol) in 60 mL of dryCH₂ Cl₂ under argon at 0° C. was added sequentially (C₂ H₅)₃ N (2.66 mL,19.1 mmol) and mesyl chloride (0.82 mL, 10.5 mmol). The mixture wasstirred at 0° C. for 1 hour and diluted with 100 mL of CH₂ Cl₂ andwashed with saturated NaHCO₃ solution (1×30 mL) and brine (1×30 mL). Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Thecrude mesylate was dissolved in 60 mL of acetone and combined with K₂CO₃ (5.0 g, 36.2 mmol). The mixture was refluxed for 4.5 hours andcooled to room temperature. The solid was filtered off and rinsed withacetone (4×40 mL). The filtrate was concentrated in vacuo andchromatographed on 120 g of Merck silica gel 60 using 2% CH₃ OH/CH₂ Cl₂as eluant to give 3.93 g (86%) of title oxazoline.

TLC: silica gel, 20% acetone in toluene, R_(f) 0.29, anisaldehyde.

C.[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl-2-oxazolyl]-

7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, methyl ester

To a stirred mixture of Part B oxazoline (3.90 g, 8.23 mmol) in 80 mL ofdry CH₂ Cl₂ under argon was added 6 g of NiO₂. The mixture was stirredat room temperature for 40 minutes at which time 4 g of NiO₂ was added.The mixture was stirred for another 70 minutes and again 2 g of NiO₂ wasadded. The mixture was stirred at room temperature for 2 hours anddiluted with 120 mL of EtOAc, 60 mL of 3M NaHSO₃ solution and 60 mL of1M sodium citrate solution. The aqueous layer was separated andextracted with EtOAc (4×150 mL). The combined EtOAc extracts were dried(MgSO₄), filtered and concentrated in vacuo. Purification was effectedby flash chromatography on 120 g of Merck silica gel 60 using 2% CH₃OH/CH₂ Cl₂ as eluant to give 1.85 g (48%) of title oxazole. TLC: silicagel, EtOAc, R_(f) 0.81, anisaldehyde.

What is claimed is:
 1. A compound having the formula ##STR195##including all stereoisomers thereof, wherein m is 1, 2 or 3;n is 0, 1,2, 3 or 4; Z is --(CH₂)₂ --, --CH═CH-- or ##STR196## wherein Y is O, asingle bond or vinyl (--CH═CH--), with the provisos that when n is 0, ifZ is ##STR197## then Y cannot be O; and when Z is --CH═CH--, n is 1, 2,3 or 4; and when Y=vinyl, n=0; R is CO₂ H, CO₂ Alkali metal, CO₂ loweralkyl, CH₂ OH, CONHSO₂ R³, CONHR^(3a) or --CH₂ -5-tetrazolyl, with theproviso that when R is --CH₂ -5-tetrazolyl, and Z is other than --(CH₂)₂--, n is 1, 2, 3 or 4; X is O, S or NH; ^(R) ¹ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl orheteroarylalkyl, or an amide ##STR198## wherein T is 1 to 12 and Ra islower alkyl, aryl, cycloalkyl or cycloalkylalkyl); R² is hydrogen, loweralkyl, aryl, or aralkyl; or R¹ and R² together with the N to which theyare linked form a 5- to 8-membered ring which contains only the single Nheteroatom; and R³ is lower alkyl, aryl or aralkyl; and R^(3a) ishydrogen, lower alkyl, aryl or aralkyl; wherein the term "aryl" byitself or as part of another group refers to a monocyclic or bicyclicaromatic group containing from 6 to 10 carbons in the ring portion,which is unsubstituted or substituted with 1 or 2 substitutents whichare lower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy,hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyland/or arylsulfonyl; the term "cycloalkyl" by itself or as part ofanother group refers to a saturated cyclic hydrocarbon group containing3 to 12 carbons, which is unsubstituted or substituted with halogen,lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" byitself or as part of another group refers to a 5-, 6- or 7-memberedsaturated ring which includes 1 or 2 heteroatoms which are nitrogen,oxygen and/or sulfur; the term "heteroaryl" by itself or as part ofanother group refers to a 5- or 6-membered aromatic ring which includes1 or 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "loweralkyl" or "alkyl" by itself or as part of another group refers to astraight or branched chain radical of up to 18 carbons which isunsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl,haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents;the term "lower alkenyl" or "alkenyl" by itself or as part of anothergroup refers to a carbon chain of up to 16 carbons containing one doublebond and which is unsubstituted or substituted with a halogensubstituent; and the term "lower alkynyl" or "alkynyl" by itself or aspart of another group refers to a carbon chain of up to 16 carbonscontaining one triple bond.
 2. The compound as defined in claim 1 havingthe formula ##STR199##
 3. The compound as defined in claim 2 having theformula ##STR200##
 4. The compound as defined in claim 2 where m=1 andn=2.
 5. The compound as defined in claim 2 having the formula ##STR201##6. The compound as defined in claim 2 having the formula ##STR202## 7.The compound as defined in claim 2 wherein R is CO₂ H, CONHSO₂ R³ or--CH₂ -5-tetrazolyl.
 8. The compound as defined in claim 3 having theformula ##STR203##
 9. The compound as defined in claim 1 wherein Z is##STR204##
 10. The compound as defined in claim 1 wherein Z is##STR205##
 11. The compound as defined in claim 1 wherein Z is##STR206##
 12. The compound as defined in claim 1 wherein Z is --(CH₂)₂-- or --CH═CH--.
 13. The compound as defined in claim 2 having the name[1S-(α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid or esters, or salts thereof;[1S-(1α,2α,3α,4α)]-3-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic839 acid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-piperidinylbutyl)amino]carbonyl]-2-oxazolyl]7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-hydroxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2-cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5,5-dimethylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-methoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α(E),4α)]-2-[3-[4-[[(4-cyclohexyl-2-butenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or saltsthereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-cyclohexylidenebutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(heptylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzeneaceticacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-cyclohexylbutyl)amino]ethyl]benzeneaceticacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(decylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1-methylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid or esters or salts thereof; [1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(8-cyclohexyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-3-[2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]ethyl]benzoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[[4-(methylthiophenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[[4-[4-methylsulfonylphenyl]butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, ethyl ester; [1S-(1α,2α,3α,4α)]-N-(4-(cyclohexylbutyl)-2-[2-[[2-(3-hydroxypropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]hept-3-yl]-4-oxazolecarboxamide;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl-N-ethylbenzenepropanamide;[1S-(1α,2α,3α,4α)]-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanamide;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylmethylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(phenylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-[2-[[3-[4-[[amino[1,1'-biphenyl]-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-4-[[(4-cyclohexylbutyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-([1S-(1α,2α,3α,4α)]-2-3-[4-[[(4-phenylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(phenylmethoxy)phenyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-4-[[hydroxyphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[4-(4-methoxyphenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-4-[[4-(4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or its potassium or sodium salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-N-methylsulfonylbenzenepropanamide;[1S-[1α,2α,3α,4α]]-2-[[3-4-[(2-propynyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoic acid, or esters or salts thereof;[1S-(1α,2α,3α(E),4α]]-2-[3-[4-[[(3-iodo-2-propenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-(hydroxy-3-iodophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or its monopotassium salt;[1S-(1α,2α,3α,4α)]-2-[[3-4-[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or its monosodium salt;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(4-cyclohexylbutyl)amino]carbonyl]-1-H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1H-imidazol-1-yl)butylamino]carbonyl]-2-oxazolyl-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4)]-2-[[3-[4-[[(1,1,-dimethylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters of salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(1,1-dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(octadecylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[5-(cyclohexylamino)-5-oxopentyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, or ester or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(5-hydroxy-5-methylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[3-[4-[[(5-carboxy-5-methylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;1S-(1α,2α,3α,4α)]-2-[[3-[4-(aminocarbonyl)-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;1S-(1α,2α(E),3α,4α)]-3-2-[[3-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenyl]-2-propenoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-fluorophenyl)-1,1-dimethylethylamino]carbonyl]2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;1S-(1α,2α,3α,4α)]-2-[[3-[4-[[4-(4-fluorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(2,2-dimethylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(2,2-dimethylpropyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(3,3-dimethylbutyl)amino]carbonyl-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[3-[4-[[[2-(4-fluorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-4-[[(2-phenylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(6-heptynylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof.
 14. The compound as defined in claim 1having the formula ##STR207##
 15. The compound as defined in claim 14where m=1 and n=2.
 16. The compound as defined in claim 1 having theformula ##STR208##
 17. The compound as defined in claim 1 having theformula ##STR209##
 18. The compound as defined in claim 14 wherein R isCO₂ H, CONHSO₂ R³ or --CH₂ -5-tetrazolyl.
 19. The compound as defined inclaim 14 having the formula ##STR210##
 20. The compound as defined inclaim 1 having the name[1S-[1α,2α(Z),3α,4α][-6-[3-[4[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S[1α,2α(Z),3α,4α]]-6-[3-4-[[(4-cyclohexylbutyl)-methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(1-pyrrolidinyl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-3-[4-(cyclohexylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;.[1S-[1α,2α(Z),3α,4α]]-6-[3-4-[[(2-cyclohexylethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-3-[4-[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-chlorophenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[4-(4-chlorophenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(6-cyclohexylhexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(propylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-butylphenyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide;4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-4-hexenamide;[1S-[1α,2α(Z),3α,4α]]-7-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid, or esters or salts thereof;[1S-[1α,2α(Z),3α,4α]]-6-[3-[4-[[[4-(2-phenylethyl)-2-thiazolyl]amino]carbonyl]-2-oxazolyl]-7-oxabycyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-[1α,2α(E),3α,4α]]-6-[3-[4-[(7,7-dimethyloctyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;1S-1α,2α(E),3α,4α]]-6-[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;[1S-(1α,2α,3α,4α)]-3-[4-[[(4-(cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoicacid, or esters or salts thereof.
 21. A method of inhibiting plateletaggregation and bronchoconstriction, which comprises administering tothe circulatory system of a mammalian host a therapeutically effectiveamount of a compound as defined in claim
 1. 22. The method as defined inclaim 21 wherein said compound is administered in an amount within therange of from about 0.1 to about 100 mg/kg.
 23. A composition forinhibiting platelet aggregation and broncoconstriction comprising atherapeutically effective amount of a compound as defined in claim 1,and a pharmaceutically acceptable carrier therefor.
 24. A method ofinhibiting platelet aggregation which comprises administering to amammalian host a therapeutically effective amount of a compound asdefined in claim
 1. 25. A method of inhibiting bronchoconstrictionassociated with asthma, which comprises administering to a mammalianhost a therapeutically effective amount of a compound as defined inclaim
 1. 26. A method for improving post-ischemic myocardial function,which comprises administering to a mammalian host in need of suchtreatment a therapeutically effective amount of a compound as defined inclaim
 1. 27. A method for treating toxemia during pregnancy, whichcomprises administering to a mammalian host in need of such treatment atherapeutically effective amount of a compound as defined in claim 1.28. A method for preventing or reducing venous thrombosis, whichcomprises administering to a mammalian host in need of such treatment atherapeutically effective amount of a compound as defined in claim 1.29. A method for preventing or reducing platelet loss duringextracorporeal circulation, which comprises administering to a mammalianhost in need of such treatment a therapeutically effective amount of acompound as defined in claim
 1. 30. A method for treating burn injuriesand/or promoting wound healing, which comprises administering to amammalian host in need of such treatment a therapeutically effectiveamount of a compound as defined in claim 1 in systemic or topical form.31. A method for reducing post-ischemic myocardial injury, whichcomprises administering to a mammalian host in need of such treatment aneffective amount of a compound as defined in claim 1 and atherapeutically effective amount of a thrombolytic agent within 6 hoursof a myocardial infarction.
 32. The method as defined in claim 31wherein said thrombolytic is t-PA, streptokinase, urokinase,prourokinase or anisoylated plasminogenstreptokinase activator complex.33. A compound having the structure ##STR211## wherein m is 1, 2 or 3; nis 0, 1, 2, 3 or 4; R_(z) is CO₂ H, CO₂ alkyl or CO₂ alkali metal; andR¹is lower alkyl, lower alkenyl, lower alkynyl, aralkyl, aryl, cycloalkyl,cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl orheteroarylalkyl, or an amide ##STR212## wherein t is 1 to 12 and Ra islower alkyl, aryl, cycloalkyl or cycloalkylalkyl); wherein the term"aryl" by itself or as part of another group refers to a monocyclic orbicyclic aromatic group containing from 6 to 10 carbons in the ringportion, which is unsubstituted or substituted with 1 or 2 substituentswhich are lower alkyl, trifluoromethyl, halogen, lower alkoxy,arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio,arylsulfinyl and/or arylsulfonyl; the term "cycloalkyl" by itself or aspart of another group refers to a saturated cyclic hydrocarbon groupcontaining 3 to 12 carbons, which is unsubstituted or substituted withhalogen, lower alkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl"by itself or as part of another group refers to a 5-, 6- or 7-memberedsaturated ring which includes 1 or 2 heteroatoms which are nitrogen,oxygen and/or sulfur; the term "heteroaryl" by itself or as part ofanother group refers to a 5- or 6-membered aromatic ring which includes1 or 2 heteroatoms which are nitrogen, oxygen or sulfur, the term "loweralkyl" or "alkyl" by itself or as part of another group refers to astraight or branched chain radical of up to 18 carbons which isunsubstituted or substituted with 1, 2 or 3 halogen, aryl, alkyl-aryl,haloaryl, cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents;the term "lower alkenyl" or "alkenyl" by itself or as part of anothergroup refers to a carbon chain of up to 16 carbons containing one doublebond and which is unsubstituted or substituted with a halogensubstituent; and the term "lower alkynyl" or "alkynyl" by itself or aspart of another group refers to a carbon chain of up to 16 carbonscontaining one triple bond.
 34. The compound as defined in claim 33having the structure ##STR213##
 35. The compound as defined in claim 33having the name[1S-([1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)oxy]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof.
 36. A compound having the formula##STR214## including all stereoisomers thereof, wherein m is 1, 2 or 3;nis 0, 1, 2, 3 or 4; Y is O, vinyl (--CHαCH--) or or a single bond, withthe proviso that when n is O, Y is a single bond; and when Y=vinyl, n=0;R is CO₂ H, CO₂ alkali metal, CO₂ lower alkyl, CONHSO₂ R³ or --CH₂-5-tetrazolyl, with the proviso that when R is --CH₂ -5-tetrazolyl, n isother than 0; X is O, S or NH; R¹ is lower alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, cycloheteroalkyl or heteroaryl; and R² ishydrogen, lower alkyl, aryl or aralkyl; wherein the term "aryl" byitself or as part of another group refers to a monocyclic or bicyclicaromatic group containing from 6 to 10 carbons in the ring portion,which is unsubstituted or substituted with 1 or 2 substituents which arelower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy,hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyland/or arylsulfonyl; the term "cycloalkyl" by itself or as part ofanother group refers to saturated cyclic hydrocarbon groups containing 3to 12 carbons, which is unsubstituted or substituted with halogen, loweralkyl, alkoxy and/or hydroxy; the term "cycloheteroalkyl" by itself oras part of another group refers to a 5-, 6- or 7-membered saturated ringwhich includes 1 or 2 heteroatoms which are nitrogen, oxygen and/orsulfur; the term "heteroaryl" by itself or as part of another grouprefers to a 5- or 6-membered aromatic ring which includes 1 to 2heteroatoms which are nitrogen, oxygen or sulfur, the term "lower alkyl"or "alkyl" by itself or as part of another group refers to a straight orbranched chain radical of up to 18 carbons which is unsubstituted orsubstituted with 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl,cycloalkyl, alkylcycloalkyl, hydroxy or carboxy substituents; the term"lower alkenyl" or "alkenyl" by itself or as part of another grouprefers to a carbon chain of up to 16 carbons containing one double bondand which is unsubstituted or substituted with a halogen substituent;and the term "lower alkynyl" or "alkynyl" by itself or as part ofanother group refers to a carbon chain of up to 16 carbons containingone triple bond.
 37. A compound having the formula ##STR215## includingall stereoisomers thereof, wherein m is 1, 2 or 3;n is 1, 2, 3 or 4; Ris CO₂ H, CO₂ alkali metal, CO₂ lower alkyl, CONHSO₂ R³ or --CH₂-5-tetrazolyl; X is O, S or NH; R¹ is lower alkyl, aryl, aralkyl,cycloalkyl, or cycloalkylalkyl; R² is hydrogen, lower alkyl, aryl, oraralkyl, or R¹ and R² together with the N to which they are linked forma 5- to 8- membered ring which contains only the single N heteroatom;and R³ is lower alkyl, aryl or aralkyl; wherein the term "aryl" byitself or as part of another group refers to monocyclic or bicyclicaromatic groups containing from 6 to 10 carbons in the ring portion,which is unsubstituted or substituted with 1 or 2 substituents which arelower alkyl, trifluoromethyl, halogen, lower alkoxy, arylalkoxy,hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyland/or arylsulfonyl; the term "cycloalkyl" by itself or as part ofanother group refers to saturated cyclic hydrocarbon groups containing 3to 12 carbons, which is unsubstituted or substituted with halogen, loweralkyl, alkoxy and/or hydroxy; and the term "lower alkyl" or "alkyl" byitself or as part of another group refers to a straight or branchedchain radicals of up to 18 carbons which is unsubstituted or substitutedwith 1, 2 or 3 halogen, aryl, alkyl-aryl, haloaryl, cycloalkyl,alkylcycloalkyl, hydroxy or carboxy substitutents.
 38. A compound havingthe name[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[2-(4-chlorophenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof.
 39. A compound having the name[1S-(1α,2α,3α,4α)]-2-[[3-[4-(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid or esters or salts thereof.
 40. A compound having the structure##STR216##
 41. A compound having the name[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[amino[1,1'-biphenyl[-4-yl]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoicacid, or esters or salts thereof.